Derivatives of 1-amino-2-cyclopropylethylboronic acid

ABSTRACT

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

PRIORITY CLAIM

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Patent Application Ser. No. 61/319,464, filed Mar. 31, 2010which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to boronic acid and boronic estercompounds useful as proteasome inhibitors. The invention also providespharmaceutical compositions comprising the compounds of the inventionand methods of using the compositions in the treatment of variousdiseases.

BACKGROUND OF THE INVENTION

Boronic acid and ester compounds display a variety of pharmaceuticallyuseful biological activities. Shenvi et al., U.S. Pat. No. 4,499,082(1985), discloses that peptide boronic acids are inhibitors of certainproteolytic enzymes. Kettner and Shenvi, U.S. Pat. No. 5,187,157 (1993),U.S. Pat. No. 5,242,904 (1993), and U.S. Pat. No. 5,250,720 (1993),describe a class of peptide boronic acids that inhibit trypsin-likeproteases. Kleeman et al., U.S. Pat. No. 5,169,841 (1992), disclosesN-terminally modified peptide boronic acids that inhibit the action ofrenin. Kinder et al., U.S. Pat. No. 5,106,948 (1992), discloses thatcertain boronic acid compounds inhibit the growth of cancer cells.Bachovchin et al., WO 07/000,5991, discloses peptide boronic acidcompounds that inhibit fibroblast activating protein. Kettner et al., WO01/02424 discloses peptide boronic acid compounds that inhibit hepatitisC viral protease.

Boronic acid and ester compounds hold particular promise as inhibitorsof the proteasome, a multicatalytic protease responsible for themajority of intracellular protein turnover. Adams et al., U.S. Pat. No.5,780,454 (1998), describes peptide boronic ester and acid compoundsuseful as proteasome inhibitors. The reference also describes the use ofboronic ester and acid compounds to reduce the rate of muscle proteindegradation, to reduce the activity of NF-κB in a cell, to reduce therate of degradation of p53 protein in a cell, to inhibit cyclindegradation in a cell, to inhibit the growth of a cancer cell, and toinhibit NF-κB dependent cell adhesion. Furet et al., WO 02/096933,Chatterjee et al., WO 05/016859, and Bernadini et al., WO 05/021558 andWO 06/08660, disclose additional boronic ester and acid compounds thatare reported to have proteasome inhibitory activity.

Ciechanover, Cell, 79: 13-21 (1994), discloses that the proteasome isthe proteolytic component of the ubiquitin-proteasome pathway, in whichproteins are targeted for degradation by conjugation to multiplemolecules of ubiquitin. Ciechanover also discloses that theubiquitin-proteasome pathway plays a key role in a variety of importantphysiological processes. Rivett et al., Biochem. J. 291:1 (1993)discloses that the proteasome displays tryptic-, chymotryptic-, andpeptidylglutamyl-peptidase activities. Constituting the catalytic coreof the 26S proteasome is the 20S proteasome. McCormack et al.,Biochemistry 37:7792 (1998), teaches that a variety of peptidesubstrates, including Suc-Leu-Leu-Val-Tyr-AMC, Z-Leu-Leu-Arg-AMC, andZ-Leu-Leu-Glu-2NA, wherein Suc is N-succinyl, AMC is7-amino-4-methylcoumarin, and 2NA is 2-naphthylamine, are cleaved by the20S proteasome.

Proteasome inhibition represents an important new strategy in cancertreatment. King et al., Science 274:1652-1659 (1996), describes anessential role for the ubiquitin-proteasome pathway in regulating cellcycle, neoplastic growth and metastasis. The authors teach that a numberof key regulatory proteins, including cyclins, and the cyclin-dependentkinases p21 and p27^(KIP1), are temporally degraded during the cellcycle by the ubiquitin-proteasome pathway. The ordered degradation ofthese proteins is required for the cell to progress through the cellcycle and to undergo mitosis.

Furthermore, the ubiquitin-proteasome pathway is required fortranscriptional regulation. Palombella et al., Cell, 78:773 (1994),teaches that the activation of the transcription factor NF-κB isregulated by proteasome-mediated degradation of the inhibitor protein10. In turn, NF-κB plays a central role in the regulation of genesinvolved in the immune and inflammatory responses. Read et al., Immunity2:493-506 (1995), teaches that the ubiquitin-proteasome pathway isrequired for expression of cell adhesion molecules, such as E-selectin,ICAM-1, and VCAM-1. Zetter, Seminars in Cancer Biology 4:219-229 (1993),teaches that cell adhesion molecules are involved in tumor metastasisand angiogenesis in vivo, by directing the adhesion and extravastationof tumor cells to and from the vasculature to distant tissue siteswithin the body. Moreover, Beg and Baltimore, Science 274:782 (1996),teaches that NF-κB is an anti-apoptotic controlling factor, andinhibition of NF-κB activation makes cells more sensitive toenvironmental stress and cytotoxic agents.

The proteasome inhibitor VELCADE® (bortezomib;N-2-pyrazinecarbonyl-L-phenylalanine-L-leucineboronic acid) is the firstproteasome inhibitor to achieve regulatory approval. Mitsiades et al.,Current Drug Targets, 7:1341 (2006), reviews the clinical studiesleading to the approval of bortezomib for the treatment of multiplemyeloma patients who have received at least one prior therapy. Fisher etal., J. Clin. Oncol., 30:4867, describes an international multi-centerPhase II study confirming the activity of bortezomib in patients withrelapsed or refractory mantle cell lymphoma. Ishii et al., Anti-CancerAgents in Medicinal Chemistry, 7:359 (2007), and Roccaro et al., Curr.Pharm. Biotech., 7:1341 (2006), discuss a number of molecular mechanismsthat may contribute to the antitumor activities of bortezomib.

Structural analysis reported by Voges et al., Annu. Rev. Biochem.,68:1015 (1999) reveals that the 20S proteasome comprises 28 subunits,with the catalytic subunits β1, β2, and β5 being responsible forpeptidylglutamyl, tryptic, and chymotryptic peptidase activity,respectively. Rivett et al., Curr. Protein Pept. Sci., 5:153 (2004)discloses that when the proteasome is exposed to certain cytokines,including IFN-γ and TNF-α, the β1, β2, and β5 subunits are replaced withalternate catalytic subunits, β1i, β2i, and β5i, to form a variant formof the proteasome known as the immunoproteasome.

Orlowski, Hematology (Am. Soc. Hematol. Educ. Program) 220 (2005),discloses that the immunoproteasome also is expressed constitutively insome cells derived from hematopoietic precursors. The author suggeststhat inhibitors specific for the immunoproteasome may allow for targetedtherapy against cancers arising from hematologic origins, therebypotentially sparing normal tissues, such as gastrointestinal andneurological tissues, from side effects.

As evidenced by the above references, the proteasome represents animportant target for therapeutic intervention. There is thus acontinuing need for new and/or improved proteasome inhibitors.

DESCRIPTION OF THE INVENTION

The present invention provides compounds that are effective inhibitorsof one or more peptidase activities of the proteasome. These compoundsare useful for inhibiting proteasome activity in vitro and in vivo, andare especially useful for the treatment of various cell proliferativediseases.

Compounds of the invention are of the general formula (I):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein:

-   A is 0, 1, or 2;-   P is hydrogen or an amino-group-blocking moiety;-   each R^(a2) independently is hydrogen, C₁₋₆ aliphatic, C₁₋₆    fluoroaliphatic, —(CH₂)_(m)—CH₂—R^(B), —(CH₂)_(m)—CH₂—NHC(═NR⁴)NH—Y,    —(CH₂)_(m)—CH₂—CON(R⁴)₂, —(CH₂)_(m)—CH₂—N(R⁴)CON(R⁴)₂,    —(CH₂)_(n)—CH(R⁶)N(R⁴)₂, —(CH₂)_(m)—CH(R⁵)—OR⁵, or    —(CH₂)_(m)—CH(R⁵)—SR⁵;-   each Y independently is hydrogen, —CN, —NO₂, or —S(O)₂—R¹⁰;-   each R^(B) independently is a substituted or unsubstituted mono- or    bicyclic ring system;-   each R⁴ independently is hydrogen or a substituted or unsubstituted    aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on the    same nitrogen atom, taken together with the nitrogen atom, form a    substituted or unsubstituted 4- to 8-membered heterocyclyl ring    having, in addition to the nitrogen atom, 0-2 ring heteroatoms    independently selected from N, O, and S;-   each R⁵ independently is hydrogen or a substituted or unsubstituted    aliphatic, aryl, heteroaryl, or heterocyclyl group;-   each R⁶ independently is a substituted or unsubstituted aliphatic,    aryl, or heteroaryl group;-   each R¹⁰ independently is C₁₋₆ aliphatic, C₆₋₁₀ aryl, or —N(R⁴)₂;-   m is 0, 1, or 2; and-   Z¹ and Z² are each independently hydroxy, alkoxy, aryloxy, or    aralkoxy; or Z¹ and Z² together form a moiety derived from a boronic    acid complexing agent.

Unless otherwise explicitly stated, the term “proteasome” is intended torefer to constitutive proteasome, immunoproteasome, or both.

The term “aliphatic” or “aliphatic group”, as used herein, means asubstituted or unsubstituted straight-chain, branched, or cyclic C₁₋₁₂hydrocarbon, which is completely saturated or which contains one or moreunits of unsaturation, but which is not aromatic. For example, suitablealiphatic groups include substituted or unsubstituted linear, branchedor cyclic alkyl, alkenyl, or alkynyl groups and hybrids thereof, such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Invarious embodiments, the aliphatic group has 1 to 12, 1 to 8, 1 to 6, 1to 4, or 1 to 3 carbons.

The terms “alkyl”, “alkenyl”, and “alkynyl”, used alone or as part of alarger moiety, refer to a straight or branched chain aliphatic grouphaving from 1 to 12 carbon atoms. For purposes of the present invention,the term “alkyl” will be used when the carbon atom attaching thealiphatic group to the rest of the molecule is a saturated carbon atom.However, an alkyl group may include unsaturation at other carbon atoms.Thus, alkyl groups include, without limitation, methyl, ethyl, propyl,allyl, propargyl, butyl, pentyl, and hexyl.

For purposes of the present invention, the term “alkenyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon double bond. Alkenyl groupsinclude, without limitation, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl,and 1-hexenyl.

For purposes of the present invention, the term “alkynyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon triple bond. Alkynyl groupsinclude, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl,and 1-hexynyl.

The term “cycloaliphatic”, used alone or as part of a larger moiety,refers to a saturated or partially unsaturated cyclic aliphatic ringsystem having from 3 to about 14 members, wherein the aliphatic ringsystem is optionally substituted. In some embodiments, thecycloaliphatic is a monocyclic hydrocarbon having 3-8 or 3-6 ring carbonatoms. Nonlimiting examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In someembodiments, the cycloaliphatic is a bridged or fused bicyclichydrocarbon having 6-12, 6-10, or 6-8 ring carbon atoms, wherein anyindividual ring in the bicyclic ring system has 3-8 members.

In some embodiments, two adjacent substituents on the cycloaliphaticring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “cycloaliphatic” includesaliphatic rings that are fused to one or more aryl, heteroaryl, orheterocyclyl rings. Nonlimiting examples include indanyl,5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring.

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to a C₆ to C₁₄aromatic hydrocarbon, comprising one to three rings, each of which isoptionally substituted. Preferably, the aryl group is a C₆₋₁₀ arylgroup. Aryl groups include, without limitation, phenyl, naphthyl, andanthracenyl. In some embodiments, two adjacent substituents on the arylring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “aryl”, as used herein,includes groups in which an aryl ring is fused to one or moreheteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the aromatic ring. Nonlimiting examples ofsuch fused ring systems include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl,indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl,benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-,or polycyclic, preferably mono-, bi-, or tricyclic, more preferablymono- or bicyclic. The term “aryl” may be used interchangeably with theterms “aryl group”, “aryl moiety”, and “aryl ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ aryl(C₁₋₆)alkyl,C₆₋₁₀ aryl(C₁₋₄)alkyl, or C₆₋₁₀ aryl(C₁₋₃)alkyl, including, withoutlimitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., heteroaralkyl, or “heteroaralkoxy”, refer to groupshaving 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to four heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Thus, when used in reference to a ring atom of a heteroaryl,the term “nitrogen” includes an oxidized nitrogen (as in pyridineN-oxide). Certain nitrogen atoms of 5-membered heteroaryl groups alsoare substitutable, as further defined below. Heteroaryl groups include,without limitation, radicals derived from thiophene, furan, pyrrole,imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole,oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyridazine,pyrimidine, pyrazine, indolizine, naphthyridine, pteridine,pyrrolopyridine, imidazopyridine, oxazolopyridine, thiazolopyridine,triazolopyridine, pyrrolopyrimidine, purine, and triazolopyrimidine. Asused herein, the phrase “radical derived from” means a monovalentradical produced by removal of a hydrogen radical from the parentheteroaromatic ring system. The radical (i.e., the point of attachmentof the heteroaryl to the rest of the molecule) may be created at anysubstitutable position on any ring of the parent heteroaryl ring system.

In some embodiments, two adjacent substituents on the heteroaryl, takentogether with the intervening ring atoms, form an optionally substitutedfused 5- to 6-membered aromatic or 4- to 8-membered non-aromatic ringhaving 0-3 ring heteroatoms selected from the group consisting of O, N,and S. Thus, the terms “heteroaryl” and “heteroar-”, as used herein,also include groups in which a heteroaromatic ring is fused to one ormore aryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the heteroaromatic ring. Nonlimiting examplesinclude indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-,bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, morepreferably mono- or bicyclic. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring”, or “heteroaryl group”,any of which terms include rings that are optionally substituted. Theterm “heteroaralkyl” refers to an alkyl group substituted by aheteroaryl, wherein the alkyl and heteroaryl portions independently areoptionally substituted.

As used herein, the terms “aromatic ring” and “aromatic ring system”refer to an optionally substituted mono-, bi-, or tricyclic group having0-6, preferably 0-4 ring heteroatoms, and having 6, 10, or 14 itelectrons shared in a cyclic array. Thus, the terms “aromatic ring” and“aromatic ring system” encompass both aryl and heteroaryl groups.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 7-membered monocyclic, or to a fused 7- to 10-membered orbridged 6- to 10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. When used in reference to a ring atom of a heterocycle, the term“nitrogen” includes a substituted nitrogen. As an example, in aheterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl). Aheterocyclic ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure, and any of the ringatoms can be optionally substituted. Examples of such saturated orpartially unsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

In some embodiments, two adjacent substituents on a heterocyclic ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein,and include groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro, including perfluorinated aliphatic groups. Examples offluoroaliphatic groups include, without limitation, fluoromethyl,difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and pentafluoroethyl.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers typically comprise an atomsuch as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—, —C(O)NH—,or a chain of atoms, such as an alkylene chain. The molecular mass of alinker is typically in the range of about 14 to 200, preferably in therange of 14 to 96 with a length of up to about six atoms. In someembodiments, the linker is a C₁₋₆ alkylene chain.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(x)—, wherein x is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms is replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group. An alkylene chain also may be substitutedat one or more positions with an aliphatic group or a substitutedaliphatic group.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is replaced with the functional group.Nonlimiting examples of suitable “interrupting functional groups”include —C(R*)═C(R*)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R⁺)—,—N(R*)—, —N(R⁺)CO—, —N(R⁺)C(O)N(R⁺)—, —N(R⁺)C(═NR⁺)—N(R⁺)—,—N(R⁺)—C(═NR⁺)—, —N(R⁺)CO₂—, —N(R⁺)SO₂—, —N(R⁺)SO₂N(R⁺)—, —OC(O)—,—OC(O)O—, —OC(O)N(R⁺)—, —C(O)—, —CO₂—, —C(O)—N(R⁺)—, —C(O)—C(O)—,—C(═NR⁺)—N(R⁺)—, —C(NR⁺)═N—, —C(═NR⁺)—O—, —C(OR*)═N—, —C(R^(o))—═N—O—,or —N(R⁺)—N(R⁺)—. Each R⁺, independently, is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or twoR⁺ on the same nitrogen atom, taken together with the nitrogen atom,form a 5-8 membered aromatic or non-aromatic ring having, in addition tothe nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S. EachR* independently is hydrogen or an optionally substituted aliphatic,aryl, heteroaryl, or heterocyclyl group.

Examples of C₃₋₆ alkylene chains that have been “interrupted” with —O—include. e.g., —CH₂OCH₂—, —CH₂—O—(CH₂)₂—, —CH₂—O—(CH₂)₃—,—CH₂—O—(CH₂)₄—, —(CH₂)₂OCH₂—, —(CH₂)—₂O(CH₂)₂—, —(CH₂)₂O(CH₂)₃—,—(CH₂)₃—O—(CH₂)—, —(CH₂)₃—O—(CH₂)₂—, and —(CH₂)₄O(CH₂)—. Other examplesof alkylene chains that are “interrupted” with functional groups include—CH₂ZCH₂—, —CH₂Z(CH₂)₂—, —CH₂Z(CH₂)₃—, —CH₂Z(CH₂)₄—, —(CH₂)₂ZCH₂—,—(CH₂)₂Z(CH₂)₂—, —(CH₂)₂Z(CH₂)₃—, —(CH₂)₃Z(CH₂)—, —(CH₂)₃Z(CH₂)₂—, and—(CH₂)₄Z(CH₂)—, wherein Z is one of the “interrupting” functional groupslisted above.

One of ordinary skill in the art will recognize that when an alkylenechain having an interruption is attached to a functional group, certaincombinations would not be sufficiently stable for pharmaceutical use.Similarly, certain combinations of T¹ and R^(2c), or T² and R^(2d),would not be sufficiently stable for pharmaceutical use. Only stable orchemically feasible compounds are within the scope of the presentinvention. A stable or chemically feasible compound is one whichmaintains its integrity long enough to be useful for therapeutic orprophylactic administration to a patient. Preferably, the chemicalstructure is not substantially altered when kept at a temperature below−70° C., below −50° C., below −20° C., below 0° C., or below 20° C., inthe absence of moisture or other chemically reactive conditions for atleast a week.

The term “substituted”, as used herein, means that a hydrogen radical ofthe designated moiety is replaced with the radical of a specifiedsubstituent, provided that the substitution results in a stable orchemically feasible compound. The term “substitutable”, when used inreference to a designated atom, means that attached to the atom is ahydrogen radical, which can be replaced with the radical of a suitablesubstituent.

The phrase “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met. Unless otherwise indicated, an optionally substituted group mayhave a substituent at each substitutable position of the group, and thesubstituents may be either the same or different.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound.

An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including the heteroaryl moiety inheteroaralkyl and heteroaralkoxy and the like) group may contain one ormore substituents. Nonlimiting examples of suitable substituents on theunsaturated carbon atom of an aryl or heteroaryl group include -halo,—NO₂, —CN, —R*, —C(R*)═C(R*)₂, —C≡C—R*, —OR*, —SR^(o), —S(O)R^(o),—SO₂R^(o), —SO₃R*, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R*, —NR⁺C(O)N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)₂, —N(R⁺)—C(═NR⁺)—R^(o), —NR⁺CO₂R^(o), —NR⁺SO₂R^(o),—NR⁺SO₂N(R⁺)₂, —O—C(O)R*, —O—CO₂R*, —OC(O)—N(R⁺)₂, —C(O)R*, —CO₂R*,—C(O)—C(O)R*, —C(O)N(R⁺)₂, —C(O)N(R⁺)—OR*, —C(O)N(R⁺)—C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R*, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR*,—N(R⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)—OR*, —C(R_(o))═N—OR*, —P(O)(R*)₂,—P(O)(OR*)₂, —O—P(O)—OR*, and —P(O)(NR⁺)—N(R⁺)₂, wherein R^(o) is anoptionally substituted aliphatic, aryl, or heteroaryl group, and R⁺ andR* are as defined above, or two adjacent substituents, taken togetherwith their intervening atoms, form a 5-6 membered unsaturated orpartially unsaturated ring having 0-3 ring atoms selected from the groupconsisting of N, O, and S.

An aliphatic group or a non-aromatic heterocyclic ring may besubstituted with one or more substituents. Examples of suitablesubstituents on the saturated carbon of an aliphatic group or of anon-aromatic heterocyclic ring include, without limitation, those listedabove for the unsaturated carbon of an aryl or heteroaryl group and thefollowing: ═O, ═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*,═N—NHCO₂R^(o), ═N—NHSO₂R^(o), or ═N—R*, where each R* and R^(o) is asdefined above.

Suitable substituents on a substitutable nitrogen atom of a heteroarylor non-aromatic heterocyclic ring include, without limitation, —R*,—N(R*)₂, —C(O)R*, —CO₂R*, —C(O)—C(O)R*—C(O)CH₂C(O)R*, —SO₂R*,—SO₂N(R*)₂, —C(═S)N(R*)₂, —C(═NH)—N(R*)₂, and —NR*SO₂R*; wherein each R*is as defined above. A ring nitrogen atom of a heteroaryl ornon-aromatic heterocyclic ring also may be oxidized to form thecorresponding N-hydroxy or N-oxide compound. A nonlimiting example ofsuch a heteroaryl having an oxidized ring nitrogen atom isN-oxidopyridyl.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%.

As used herein, the term “comprises” means “includes, but is not limitedto.”

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention. Unlessotherwise stated, structures depicted herein are also meant to includeall geometric (or conformational) isomers, i.e., (Z) and (E) double bondisomers and (Z) and (E) conformational isomers, as well as allstereochemical forms of the structure; i.e., the R and S configurationsfor each asymmetric center. Therefore, single stereochemical isomers aswell as enantiomeric and diastereomeric mixtures of the presentcompounds are within the scope of the invention. When a mixture isenriched in one stereoisomer relative to another stereoisomer, themixture may contain, for example, an enantiomeric excess of at least50%, 75%, 90%, 99%, or 99.5%.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructure except for the replacement of a hydrogen atom by a deuteriumor tritium, or the replacement of a carbon atom by a ¹³C— or¹⁴C-enriched carbon are within the scope of the invention.

In the compounds of formula (I), the variable P is hydrogen or anamino-group-blocking moiety. Non-limiting examples ofamino-group-blocking moieties can be found in P. G. M. Wuts and T. W.Greene, Greene's Protective Groups in Organic Synthesis (4^(th) ed.),John Wiley & Sons, NJ (2007), and include, e.g., acyl, sulfonyl,oxyacyl, and aminoacyl groups.

In some embodiments, P is R^(c)—C(O)—, R^(c)—O—C(O)—,R^(c)—N(R^(4c))—C(O)—, R^(c)—S(O)₂—, or R^(c)—N(R^(4c))—S(O)₂—, whereR^(c) is selected from the group consisting of C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, —R^(D), -T¹-R^(D), and -T¹-R^(2c), and the variablesT¹, R^(D), R^(2c), and R^(4c) have the values described below.

The variable R^(4c) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ar(C₁₋₄)alkyl, the aryl portion of which is substituted orunsubstituted. In some embodiments, R^(4c) is hydrogen or C₁₋₄ alkyl. Incertain particular embodiments, R^(4c) is hydrogen.

The variable T¹ is a C₁₋₆ alkylene chain substituted with 0-2independently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R⁵)═C(R⁵)—, —C≡C—, or —O—. Each R^(3a)independently is selected from the group consisting of —F, —OH, —O(C₁₋₄alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₄ alkyl), —CO₂H, —CO₂(C₁₋₄ alkyl),—C(O)NH₂, and —C(O)—NH(C₁₋₄ alkyl). Each R^(3b) independently is a C₁₋₃aliphatic optionally substituted with R^(3a) or R⁷. Each R⁷ is asubstituted or unsubstituted aromatic group. In some embodiments, T¹ isa C₁₋₄ alkylene chain.

The variable R^(2a) is halo, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, or—C(O)N(R⁴)₂, where:

each R⁴ independently is hydrogen or an optionally substitutedaliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on thesame nitrogen atom, taken together with the nitrogen atom, form anoptionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S;

each R⁵ independently is hydrogen or an optionally substitutedaliphatic, aryl, heteroaryl, or heterocyclyl group; and

each R⁶ independently is an optionally substituted aliphatic, aryl, orheteroaryl group.

The variable R^(D) is a substituted or unsubstituted aromatic,heterocyclyl, or cycloaliphatic ring, any of which is optionally fusedto a substituted or unsubstituted aromatic, heterocyclyl orcycloaliphatic ring. Each saturated ring carbon atom in R^(D) isunsubstituted or is substituted with ═O, R^(d), or R^(8d). Eachunsaturated ring carbon in R^(D) is unsubstituted or is substituted withR^(d) or R^(8d). Each substitutable ring nitrogen atom in R^(D) isunsubstituted or is substituted with —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶,—SO₂R⁶, —SO₂N(R⁴)₂, C₁₋₄ aliphatic, a substituted or unsubstituted C₆₋₁₀aryl, or a C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which is substitutedor unsubstituted.

In some embodiments, one or two saturated ring carbon atoms in R^(D) aresubstituted with ═O; the remaining substitutable ring carbon atoms inR^(D) are substituted with 0-2 R^(d) and 0-2 R^(8d); and eachsubstitutable ring nitrogen atom in R^(D) is unsubstituted or issubstituted with —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, C₁₋₄aliphatic, a substituted or unsubstituted C₆₋₁₀ aryl, or a C₆₋₁₀ar(C₁₋₄)alkyl, the aryl portion of which is substituted orunsubstituted.

Each R^(d) independently is selected from the group consisting of C₁₋₆aliphatic, C₁₋₆ fluoroaliphatic, halo, —R^(1d), —R^(2d), -T²-R^(1d), and-T²-R^(2d), where the variables T², R^(1d), R^(2d), and R^(8d) have thevalues described below.

T² is a C₁₋₆ alkylene chain substituted with 0-2 independently selectedR^(3a) or R^(3b), wherein the alkylene chain optionally is interruptedby —C(R⁵)═C(R⁵)—, —C≡C—, or —O—. The variables R^(3a) and R^(3b) havethe values described above.

Each R^(1d) independently is a substituted or unsubstituted aryl,heteroaryl, heterocyclyl, or cycloaliphatic ring.

Each R^(2d) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C═C—R⁵, —OR⁵,—SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂,—C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, or—C(═NR⁴)—N(R⁴)₂.

Each R^(8d) independently is selected from the group consisting of C₁₋₄aliphatic, C₁₋₄ fluoroaliphatic, halo, —OH, —O(C₁₋₄ aliphatic), —NH₂,—NH(C₁₋₄ aliphatic), and —N(C₁₋₄ aliphatic)₂.

In some embodiments, R^(D) is a substituted or unsubstituted mono- orbicyclic ring system selected from the group consisting of furanyl,thienyl, pyrrolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl,benzothiazolyl, indolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,indazolyl, purinyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, and dihydrobenzoxazinyl. Insome embodiments, R^(D) is a substituted or unsubstituted mono- orbicyclic ring system selected from the group consisting of phenyl,pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl,benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, and dihydrobenzoxazinyl. Insome embodiments, R^(D) is a substituted or unsubstituted mono- orbicyclic ring system selected from the group consisting of phenyl,pyridinyl, pyrazinyl, benzothiazolyl, indolyl, isoquinolinyl,tetrahydroquinoxalinyl, oxodihydroindolyl, oxodihydrobenzoxazinyl, anddihydrobenzoxazinyl.

In some embodiments, R^(D) is a substituted or unsubstituted tricyclicring system selected from the group consisting of dibenzofuranyl,dibenzothienyl, indenopyridyl, benzofuropyridyl, benzothienopyridyl,benzofuropyrazinyl, S,S-dioxodibenzothiophenyl, xanthenyl,dibenzo-1,4-dioxinyl, phenoxathiinyl, phenoxazinyl, phenothiazinyl,pyridoindolyl, acridinyl, and phenanthridinyl. In some embodiments,R^(D) is a substituted or unsubstituted tricyclic ring system selectedfrom the group consisting of benzofuropyridyl, pyridoindolyl, andbenzofuropyrazinyl. In some embodiments, R^(D) is substituted orunsubstituted benzofuropyridyl.

In some embodiments, one or two saturated ring carbon atoms in R^(D) aresubstituted with ═O, and the remaining substitutable ring carbon atomsin R^(D) are substituted with 0-1 R^(d) and 0-2 R^(8d), wherein:

each R^(d) independently is selected from the group consisting of C₁₋₆aliphatic, C₁₋₆ fluoroaliphatic, halo, —R^(1d), —R^(2d), -T²-R^(1d), and-T²-R^(2d);

T² is a C₁₋₃ alkylene chain that is unsubstituted or is substituted withR^(3a) or R^(3b);

each R^(1d) independently is a substituted or unsubstituted aryl,heteroaryl, heterocyclyl, or cycloaliphatic ring; and

each R^(2d) independently is −OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —O—C(O)R⁵, —OC(O)N(R⁴)₂, —C(O)R⁵,—CO₂R⁵, or —C(O)N(R⁴)₂.

In some embodiments, the variable R^(d) has the formula -Q-R^(E), whereQ is —O—, —NH—, —S(O)—, —S(O)₂—, —C(O)—, or —CH₂—, and R^(E) is asubstituted or unsubstituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic ring. In some embodiments, R^(E) is a substituted orunsubstituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl,benzothiazolyl, benzimidazolyl, indolyl, piperidinyl, piperazinyl, ormorpholinyl ring.

In some embodiments, the variable R^(d) has the formula -Q-R^(E), whereQ is a bond and R^(E) is a substituted or unsubstituted aryl,heteroaryl, heterocyclyl, or cycloaliphatic ring. In some embodiments,R^(E) is a substituted or unsubstituted phenyl, pyridinyl, pyrimidinyl,pyrazinyl, quinolinyl, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl,benzimidazolyl, indolyl, piperidinyl, piperazinyl, or morpholinyl ring.In some embodiments, R^(E) is a substituted or unsubstituted phenyl,pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl,piperidinyl, piperazinyl, or morpholinyl ring.

In some embodiments, P has the formula R^(c)—C(O)—, where R^(c) is C₁₋₄alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄) alkyl, the aryl portion ofwhich is substituted or unsubstituted. In certain such embodiments, P isselected from the group consisting of acetyl, trifluoroacetyl, andphenylacetyl.

In some other embodiments, P has the formula R^(D)—C(O)—, where R^(D) isa substituted or unsubstituted phenyl, pyridinyl, pyrazinyl,pyrimidinyl, quinolinyl, or quinoxalinyl. In certain embodiments, P hasthe formula R^(D)—C(O)—, where R^(D) is a phenyl, pyridinyl, pyrazinyl,pyrimidinyl, naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl, ordihydrobenzoxazinyl substituted with 0-1 R^(d) and 0-2 R^(8d). Incertain particular embodiments, P has the formula R^(D)—C(O)—, whereR^(D) is a phenyl, or pyrazinyl, substituted with 0-1 R^(d) and 0-2R^(8d). In certain particular embodiments, P has the formulaR^(D)—C(O)—, where R^(D) is a pyridinyl, pyrazinyl, or pyrimidinyl,which is substituted with a substituent of formula —O—R^(E), and R^(E)is a substituted or unsubstituted phenyl. In certain other particularembodiments, P has the formula R^(D)—C(O)—, where R^(D) is a phenyl,which is substituted with a substituent of formula —O—R^(E), and R^(E)is a substituted or unsubstituted pyridinyl, pyrazinyl, or pyrimidinyl.

In some other embodiments, P has the formula R^(c)—SO₂—, where R^(c) is—R^(D) or -T¹-R^(D), where T¹ is C₁₋₄ alkylene and R^(D) is a phenyl,pyridinyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, isoquinolinyl,quinoxalinyl, benzimidazolyl, benzothiazolyl, indolyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, or dihydrobenzoxazinylsubstituted with 0-1 R^(d) and 0-2 R^(8d). In some embodiments, P hasthe formula R^(D)—SO₂—, where R^(D) is a substituted or unsubstitutedphenyl, pyridinyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl,isoquinolinyl, quinoxalinyl, benzimidazolyl, benzothiazolyl, indolyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, or dihydrobenzoxazinyl. Incertain embodiments, P has the formula R^(D)—SO₂—, where R^(D) is aphenyl, pyridinyl, pyrazinyl, isoquinolinyl, benzothiazolyl, indolyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, or dihydrobenzoxazinylsubstituted with 0-1 R^(d) and 0-2 R^(8d). In certain particularembodiments, P has the formula R^(D)—SO₂—, where R^(D) is a pyridinyl,pyrazinyl, or pyrimidinyl, which is substituted with a substituent offormula —O—R^(E), and R^(E) is a substituted or unsubstituted phenyl. Incertain other particular embodiments, P has the formula R^(D)—SO₂—,where R^(D) is a phenyl, which is substituted with a substituent offormula —O—R^(E), and R^(E) is a substituted or unsubstituted pyridinyl,pyrazinyl, pyrimidinyl, quinolinyl, benzothiazolyl, benzimidazolyl, orindolyl.

Each variable R^(a2) is independently C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, —(CH₂)_(m)—CH₂—R^(B), —(CH₂)_(m)—CH₂—NHC(═NR⁴)NH—Y,—(CH₂)_(m)—CH₂—CON(R⁴)₂, (CH₂)_(m)—CH₂—N(R⁴)CON(R⁴)₂,—(CH₂)_(m)—CH(R⁶)N(R⁴)₂, —(CH₂)_(m)—CH(R⁵)—OR⁵, or—(CH₂)_(m)—CH(R⁵)—SR⁵, where the variables R⁴, R⁵, and R⁶ have thevalues described above, and the variables R^(B) and in have the valuesdescribed below.

Each R^(B), independently, is a substituted or unsubstituted mono- orbicyclic ring system. In some embodiments, each R^(B) independently is asubstituted or unsubstituted phenyl, pyridyl, indolyl, benzimidazolyl,naphthyl, quinolinyl, quinoxalinyl, or isoquinolinyl ring. In certainembodiments, R^(B) is a substituted or unsubstituted phenyl ring.

The variable m is 0, 1, or 2. In some embodiments, m is 0 or 1.

In some embodiments, each R^(a2) is independently C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, or —(CH₂)_(m)—CH₂—R^(B), and m is 0 or 1. In some suchembodiments, R^(B) is substituted or unsubstituted phenyl. In certainembodiments, R^(a2) is isopropyl, benzyl, or phenethyl.

The variable A is 0, 1, or 2. In some embodiments, A is 0 or 1. Incertain embodiments, A is 0.

In some embodiments, the invention relates to a compound of formula (I)characterized by formula (I-A):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein each of the variables P, R^(a2), A, Z¹, and Z² has the valuesand preferred values described above for formula (I).

In certain embodiments, the invention relates to a compound of formula(I) characterized by formula (I-B):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein each of the variables P, R^(a2), A, Z¹, and Z² has the valuesand preferred values described above for formula (I).

In certain particular embodiments, the invention relates to a compoundof formula (I), characterized by formula (II):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein each of the variables P, Z¹, and Z² has the values and preferredvalues described above for formula (I).

In some embodiments, the invention relates to a compound of formula(II), wherein P has the formula R^(D)—C(O)—, where R^(D) is asubstituted or unsubstituted phenyl, pyridinyl, pyrazinyl, pyrimidinyl,quinolinyl, or quinoxalinyl. In certain embodiments, P has the formulaR^(D)—C(O)—, where R^(D) is a phenyl, pyridinyl, pyrazinyl, pyrimidinyl,naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl, ordihydrobenzoxazinyl substituted with 0-1 R^(d) and 0-2 R^(8d). Incertain particular embodiments, P has the formula R^(D)—C(O)—, whereR^(D) is a phenyl, or pyrazinyl, substituted with 0-1 R^(d) and 0-2R^(8d). In some such embodiments, R^(d) is a substituted orunsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring,and each R^(8d) independently is C₁₄ aliphatic, C₁₋₄ fluoroaliphatic, orhalo.

In certain particular embodiments, P has the formula R^(D)—C(O)—, whereR^(D) is a pyridinyl, pyrazinyl, or pyrimidinyl, which is substitutedwith a substituent of formula —O—R^(E), and R^(E) is a substituted orunsubstituted phenyl. In certain other particular embodiments, P has theformula R^(D)—C(O)—, where R^(D) is a phenyl, which is substituted witha substituent of formula —O—R^(E), and R^(E) is a substituted orunsubstituted pyridinyl, pyrazinyl, or pyrimidinyl.

In some other embodiments, the invention relates to a compound offormula (II), wherein P has the formula R^(c)—SO₂—, where R^(c) is—R^(D) or -T¹-R^(D), where T¹ is C₁₋₄ alkylene and R^(D) is a phenyl,pyridinyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, isoquinolinyl,quinoxalinyl, benzimidazolyl, benzothiazolyl, indolyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, or dihydrobenzoxazinylsubstituted with 0-1 R^(d) and 0-2 R^(8d). In some embodiments, P hasthe formula R^(D)—SO₂—, where R^(D) is a substituted or unsubstitutedphenyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl,quinoxalinyl, benzimidazolyl, benzothiazolyl, indolyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, or dihydrobenzoxazinyl. Incertain embodiments, P has the formula R^(D)—SO₂—, where R^(D) is aphenyl, pyridinyl, pyrazinyl, isoquinolinyl, benzothiazolyl, indolyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, or dihydrobenzoxazinylsubstituted with 0-1 R^(d) and 0-2 R^(8d). In some such embodiments,R^(d) is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl,or cycloaliphatic ring, and each R^(8d) independently is C₁₋₄ aliphatic,C₁₋₄ fluoroaliphatic, or halo. In certain embodiments, P has the formulaR^(D)—SO₂—, where R^(D) is a phenyl substituted with 0-1 R^(d), and

R^(d) is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl,or cycloaliphatic ring. In certain such embodiments, P has the formulaR^(D)—SO₂—, where R^(D) is a phenyl substituted with 1 R^(d), andR^(d) is a substituted or unsubstituted oxazolyl, thiazolyl, orimidazolyl; wherein if substituted, R^(d) is substituted with 1 R^(dd);and R^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

In certain particular embodiments, P has the formula R^(D)—SO₂—, whereR^(D) is a pyridinyl, pyrazinyl, or pyrimidinyl, which is substitutedwith a substituent of formula —O—R^(E), and R^(E) is a substituted orunsubstituted phenyl. In certain other particular embodiments, P has theformula R^(D)—SO₂—, where R^(D) is a phenyl, which is substituted with asubstituent of formula —O—R^(E), and R^(E) is a substituted orunsubstituted pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl,benzothiazolyl, benzimidazolyl, or indolyl. In certain such embodiments,R^(E) is a substituted or unsubstituted pyridinyl, pyrazinyl,pyrimidinyl, quinolinyl, benzothiazolyl, benzimidazolyl, or indolyl;wherein if substituted, R^(E) is substituted with 1-2 R^(dd). In somesuch embodiments, each R^(dd) is independently C₁₄ aliphatic, C₁₋₄fluoroaliphatic, or halo. In certain such embodiments, R^(E) is asubstituted or unsubstituted pyridinyl; wherein if substituted, R^(E) issubstituted with 1 R^(dd). In some such embodiments, R^(dd) is methyl,ethyl, trifluoromethyl, chloro, or fluoro.

In certain particular embodiments, P has the formula R^(D)—SO₂—, whereR^(D) is phenyl, which is substituted with a substitutent of formula—C(O)—R^(E), and R^(E) is a substituted or unsubstituted pyridinyl,pyrazinyl, or pyrimidinyl. In certain such embodiments, R^(E) is asubstituted or unsubstituted pyridinyl, pyrazinyl, or pyrimidinyl;wherein if substituted, R^(E) is substituted with 1-2 R^(dd). In somesuch embodiments, each R^(dd) is independently C₁₄ aliphatic, C₁₋₄fluoroaliphatic, or halo. In certain such embodiments, R^(E) is asubstituted or unsubstituted pyridinyl; wherein if substituted, R^(E) issubstituted with 1 R^(dd). In some such embodiments, R^(dd) is methyl,ethyl, trifluoromethyl, chloro, or fluoro.

In certain other particular embodiments, P has the formula R^(D)—SO₂—,where R^(D) is phenyl, which is substituted with a substitutent offormula —S(O)—R^(E), and R^(E) is a substituted or unsubstitutedpyridinyl, pyrazinyl, or pyrimidinyl. In certain other particularembodiments, P has the formula R^(D)—SO₂—, where R^(D) is phenyl, whichis substituted with a substitutent of formula —S(O)₂—R^(E), and R^(E) isa substituted or unsubstituted pyridinyl, pyrazinyl, or pyrimidinyl. Incertain other particular embodiments, P has the formula R^(D)—SO₂—,where R^(D) is phenyl, which is substituted with a substitutent offormula —NH—R^(E), and R^(E) is a substituted or unsubstitutedpyridinyl, pyrazinyl, or pyrimidinyl.

In certain embodiments, the invention relates to a compound of formula(I), characterized by formula (II):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein each of the variables Z¹ and Z² has the values and preferredvalues described herein for formula (I);

P is R^(D)—SO₂—;

R^(D) is phenyl substituted with 0-1 R^(d); and

R^(d) is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl,or cycloaliphatic ring.

In certain such embodiments:

R^(D) is phenyl substituted with 1 R^(d);

R^(d) is substituted or unsubstituted oxazolyl, thiazolyl, orimidazolyl;

wherein if substituted, R^(d) is substituted with 1 R^(dd); and

R^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

In certain embodiments, the invention relates to a compound of formula(I), characterized by formula (II):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein each of the variables Z¹ and Z² has the values and preferredvalues described herein for formula (I);

P is R^(D)—SO₂—;

R^(D) is a phenyl substituted with —O—R^(E);

R^(E) is a substituted or unsubstituted pyridinyl, pyrazinyl,pyrimidinyl, quinolinyl, benzothiazolyl, benzimidazolyl, or indolyl;

wherein if substituted, R^(E) is substituted with 1-2 R^(dd); and

each R^(dd) is independently C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, orhalo.

In certain such embodiments:

R^(E) is a substituted or unsubstituted pyridinyl;

wherein if substituted, R^(E) is substituted with 1 R^(dd); and

R^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

In certain embodiments, the invention relates to a compound of formula(I), characterized by formula (II):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein each of the variables Z¹ and Z² has the values and preferredvalues described herein for formula (I);

P is R^(D)—SO₂—;

R^(D) is a phenyl substituted with —C(O)—R^(E),

R^(E) is a substituted or unsubstituted pyridinyl, pyrazinyl, orpyrimidinyl;

wherein if substituted, R^(E) is substituted with 1-2 R^(dd); and

each R^(dd) is independently C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, orhalo.

In certain such embodiments:

R^(E) is a substituted or unsubstituted pyridinyl;

wherein if substituted, R^(E) is substituted with 1 R^(dd); and

R^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

Representative examples of compounds of formula (I) are shown in Table1.

TABLE 1 Proteasome Inhibitors

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

The compounds in Table 1 above may also be identified by the followingchemical names:

1 ((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 2((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 3{(1R)-2-cyclopropyl-1-[((2S)-2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid 4[(1R)-1-({(2S)-2-[(1,3-benzothiazol-6-ylsulfonyl)amino]-3-phenylpropanoyl}amino)-2-cyclopropylethyl]boronic acid 5((1R)-2-cyclopropyl-1-{[(2S)-2-({[3-(2-methyl-1,3-thiazol-4-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acid 6((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1,3-oxazol-5-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acid 7{(1R)-2-cyclopropyl-1-[((2S)-3-phenyl-2-{[(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)sulfonyl]amino}propanoyl)amino]ethyl}boronic acid 8{(1R)-2-cyclopropyl-1-[((2S)-2-{[(6-phenoxypyridin-3-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid 9[(1R)-2-cyclopropyl-1-({(2S)-2-[(2,5-dichlorobenzoyl)amino]-3-phenylpropanoyl}amino)ethyl]boronic acid 10{(1R)-2-cyclopropyl-1-[((2S)-2-{[(1-methyl-1H-indol-4-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid 11{(1R)-2-cyclopropyl-1-[((2S)-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]amino}-3- phenylpropanoyl)amino]ethyl}boronicacid 12 [(1R)-2-cyclopropyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)ethyl]boronic acid 13{(1R)-2-cyclopropyl-1-[((2S)-2-{[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid 14((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-4-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 15{(1R)-1-[((2S)-2-{[(6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]-2-cyclopropylethyl}boronic acid 16((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[3-(pyridin-2-ylcarbonyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 17[(1R)-2-cyclopropyl-1-({(2S)-2-[(isoquinolin-5-ylsulfonyl)amino]-3-phenylpropanoyl}amino)ethyl]boronic acid 18((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylsulfinyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 19((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylsulfonyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 20((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 21[(1R)-1-({(2S)-2-[([1]benzofuro[2,3-b]pyridin-6-ylsulfonyl)amino]-3-phenylpropanoyl}amino)-2-cyclopropylethyl]boronic acid 22((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-2-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 23((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-4-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 24((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(quinolin-3-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 25((1R)-1-{[(2S)-2-({[4-(1,3-benzothiazol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}-2-cyclopropylethyl)boronic acid 26((1R)-1-{[(2S)-2-({[4-(1H-benzimidazol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}-2-cyclopropylethyl)boronic acid 27((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1H-imidazol-5-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acid 28((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1H-indol-5-yloxy)phenyl]sulfonyl}amino)-3- phenylpropanoyl]amino}ethyl)boronic acid29 {(1R)-2-cyclopropyl-1-[((2S)-2-{[(2-phenoxypyrimidin-5-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid 30((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyrimidin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 31{(1R)-2-cyclopropyl-1-[((2S)-2-{[(5-phenoxypyrazin-2-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid 32((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyrazin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid 33{(1R)-2-cyclopropyl-1-[((2S)-2-{[(5-phenoxypyridin-2-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid

The corresponding pinanediol esters, mannitol esters, and citrate estersof each of the Compounds 1-33 are listed in Table 2 below. For example,Compound 1-A is the corresponding pinanediol ester of Compound 1;Compound 1-B is the corresponding mannitol ester of Compound 1; Compound1-C is the corresponding citrate ester of Compound 1, and so on. Thepinanediol esters and mannitol esters may be synthesized by proceduresoutlined in the Experimental Section below. The citrate esters may besynthesized by procedures described in Elliott et al., WO 09/154,737,herein incorporated by reference.

TABLE 2 Proteasome Inhibitors  1-A((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester  1-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester  1-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester  2-A ((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester  2-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester  2-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester  3-A {(1R)-2-cyclopropyl-1-[((2S)-2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid pinanediolester  3-B {(1R)-2-cyclopropyl-1-[((2S)-2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid D-mannitolester  3-C {(1R)-2-cyclopropyl-1-[((2S)-2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid citrateester  4-A [(1R)-1-({(2S)-2-[(1,3-benzothiazol-6-ylsulfonyl)amino]-3-phenylpropanoyl}amino)-2-cyclopropylethyl]boronic acid pinanediol ester 4-B [(1R)-1-({(2S)-2-[(1,3-benzothiazol-6-ylsulfonyl)amino]-3-phenylpropanoyl}amino)-2-cyclopropylethyl]boronic acid D-mannitol ester 4-C [(1R)-1-({(2S)-2-[(1,3-benzothiazol-6-ylsulfonyl)amino]-3-phenylpropanoyl}amino)-2-cyclopropylethyl]boronic acid citrate ester 5-A ((1R)-2-cyclopropyl-1-{[(2S)-2-({[3-(2-methyl-1,3-thiazol-4-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidpinanediol ester  5-B((1R)-2-cyclopropyl-1-{[(2S)-2-({[3-(2-methyl-1,3-thiazol-4-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acid D-mannitol ester  5-C((1R)-2-cyclopropyl-1-{[(2S)-2-({[3-(2-methyl-1,3-thiazol-4-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidcitrate ester  6-A ((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1,3-oxazol-5-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidpinanediol ester  6-B ((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1,3-oxazol-5-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acid D-mannitol ester  6-C ((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1,3-oxazol-5-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidcitrate ester  7-A{(1R)-2-cyclopropyl-1-[((2S)-3-phenyl-2-{[(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)sulfonyl]amino}propanoyl)amino]ethyl}boronic acidpinanediol ester  7-B{(1R)-2-cyclopropyl-1-[((2S)-3-phenyl-2-{[(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)sulfonyl]amino}propanoyl)amino]ethyl}boronic acid D-mannitol ester  7-C{(1R)-2-cyclopropyl-1-[((2S)-3-phenyl-2-{[(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)sulfonyl]amino}propanoyl)amino]ethyl}boronic acid citrateester  8-A{(1R)-2-cyclopropyl-1-[((2S)-2-{[(6-phenoxypyridin-3-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid pinanediol ester  8-B{(1R)-2-cyclopropyl-1-[((2S)-2-{[(6-phenoxypyridin-3-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid D-mannitol ester  8-C{(1R)-2-cyclopropyl-1-[((2S)-2-{[(6-phenoxypyridin-3-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid citrate ester  9-A[(1R)-2-cyclopropyl-1-({(2S)-2-[(2,5-dichlorobenzoyl)amino]-3-phenylpropanoyl}amino)ethyl]boronic acid pinanediol ester  9-B[(1R)-2-cyclopropyl-1-({(2S)-2-[(2,5-dichlorobenzoyl)amino]-3-phenylpropanoyl}amino)ethyl]boronic acid D-mannitol ester  9-C[(1R)-2-cyclopropyl-1-({(2S)-2-[(2,5-dichlorobenzoyl)amino]-3-phenylpropanoyl}amino)ethyl]boronic acid citrate ester 10-A{(1R)-2-cyclopropyl-1-[((2S)-2-{[(1-methyl-1H-indol-4-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid pinanediol ester 10-B{(1R)-2-cyclopropyl-1-[((2S)-2-{[(1-methyl-1H-indol-4-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid D-mannitol ester 10-C{(1R)-2-cyclopropyl-1-[((2S)-2-{[(1-methyl-1H-indol-4-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid citrate ester 11-A{(1R)-2-cyclopropyl-1-[((2S)-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acidpinanediol ester 11-B{(1R)-2-cyclopropyl-1-[((2S)-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid D-mannitol ester 11-C{(1R)-2-cyclopropyl-1-[((2S)-2-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid citrateester 12-A [(1R)-2-cyclopropyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)ethyl]boronic acid pinanediol ester12-B [(1R)-2-cyclopropyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)ethyl]boronic acid D-mannitol ester12-C [(1R)-2-cyclopropyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)ethyl]boronic acid citrate ester 13-A{(1R)-2-cyclopropyl-1-[((2S)-2-{[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid pinanediolester 13-B{(1R)-2-cyclopropyl-1-[((2S)-2-{[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid D-mannitolester 13-C{(1R)-2-cyclopropyl-1-[((2S)-2-{[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid citrateester 14-A ((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-4-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 14-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-4-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 14-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-4-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester 15-A{(1R)-1-[((2S)-2-{[(6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]-2-cyclopropylethyl}boronicacid pinanediol ester 15-B{(1R)-1-[((2S)-2-{[(6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]-2-cyclopropylethyl}boronicacid D-mannitol ester 15-C{(1R)-1-[((2S)-2-{[(6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]-2-cyclopropylethyl}boronicacid citrate ester 16-A((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[3-(pyridin-2-ylcarbonyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 16-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[3-(pyridin-2-ylcarbonyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 16-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[3-(pyridin-2-ylcarbonyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidcitrate ester 17-A[(1R)-2-cyclopropyl-1-({(2S)-2-[(isoquinolin-5-ylsulfonyl)amino]-3-phenylpropanoyl}amino)ethyl]boronic acid pinanediol ester 17-B[(1R)-2-cyclopropyl-1-({(2S)-2-[(isoquinolin-5-ylsulfonyl)amino]-3-phenylpropanoyl}amino)ethyl]boronic acid D-mannitol ester 17-C[(1R)-2-cyclopropyl-1-({(2S)-2-[(isoquinolin-5-ylsulfonyl)amino]-3-phenylpropanoyl}amino)ethyl]boronic acid citrate ester 18-A((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylsulfinyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 18-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylsulfinyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidD-mannitol ester 18-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylsulfinyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidcitrate ester 19-A(1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylsulfonyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 19-B(1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylsulfonyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 19-C(1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylsulfonyl)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidcitrate ester 20-A((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 20-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 20-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-3-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester 21-A[(1R)-1-({(2S)-2-[([1]benzofuro[2,3-b]pyridin-6-ylsulfonyl)amino]-3-phenylpropanoyl}amino)-2-cyclopropylethyl]boronic acid pinanediol ester21-B[(1R)-1-({(2S)-2-[([1]benzofuro[2,3-b]pyridin-6-ylsulfonyl)amino]-3-phenylpropanoyl}amino)-2-cyclopropylethyl]boronic acid D-mannitol ester21-C[(1R)-1-({(2S)-2-[([1]benzofuro[2,3-b]pyridin-6-ylsulfonyl)amino]-3-phenylpropanoyl}amino)-2-cyclopropylethyl]boronic acid citrate ester22-A ((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-2-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 22-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-2-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 22-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-2-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester 23-A ((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-4-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 23-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-4-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 23-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyridin-4-ylamino)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester 24-A ((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(quinolin-3-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 24-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(quinolin-3-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 24-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(quinolin-3-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester 25-A((1R)-1-{[(2S)-2-({[4-(1,3-benzothiazol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}-2-cyclopropylethyl)boronic acid pinanediol ester25-B((1R)-1-{[(2S)-2-({[4-(1,3-benzothiazol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}-2-cyclopropylethyl)boronic acid D-mannitol ester25-C((1R)-1-{[(2S)-2-({[4-(1,3-benzothiazol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}-2-cyclopropylethyl)boronic acid citrate ester26-A((1R)-1-{[(2S)-2-({[4-(1H-benzimidazol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}-2-cyclopropylethyl)boronic acid pinanediol ester26-B((1R)-1-{[(2S)-2-({[4-(1H-benzimidazol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}-2-cyclopropylethyl)boronic acid D-mannitol ester26-C((1R)-1-{[(2S)-2-({[4-(1H-benzimidazol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}-2-cyclopropylethyl)boronic acid citrate ester27-A ((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1H-imidazol-5-yl)phenyl]sufonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidpinanediol ester 27-B((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1H-imidazol-5-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acid D-mannitol ester 27-C ((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1H-imidazol-5-yl)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidcitrate ester 28-A ((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1H-indol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidpinanediol ester 28-B ((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1H-indol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidD-mannitol ester 28-C ((1R)-2-cyclopropyl-1-{[(2S)-2-({[4-(1H-indol-5-yloxy)phenyl]sulfonyl}amino)-3-phenylpropanoyl]amino}ethyl)boronic acidcitrate ester 29-A{(1R)-2-cyclopropyl-1-[((2S)-2-{[(2-phenoxypyrimidin-5-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid pinanediolester 29-B {(1R)-2-cyclopropyl-1-[((2S)-2-{[(2-phenoxypyrimidin-5-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid D-mannitolester 29-C {(1R)-2-cyclopropyl-1-[((2S)-2-{[(2-phenoxypyrimidin-5-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid citrateester 30-A ((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyrimidin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 30-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyrimidin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 30-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyrimidin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester 31-A{(1R)-2-cyclopropyl-1-[((2S)-2-{[(5-phenoxypyrazin-2-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid pinanediol ester 31-B{(1R)-2-cyclopropyl-1-[((2S)-2-{[(5-phenoxypyrazin-2-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid D-mannitol ester 31-C{(1R)-2-cyclopropyl-1-[((2S)-2-{[(5-phenoxypyrazin-2-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid citrate ester 32-A((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyrazin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acidpinanediol ester 32-B((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyrazin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid D-mannitol ester 32-C((1R)-2-cyclopropyl-1-{[(2S)-3-phenyl-2-({[4-(pyrazin-2-yloxy)phenyl]sulfonyl}amino)propanoyl]amino}ethyl)boronic acid citrateester 33-A{(1R)-2-cyclopropyl-1-[((2S)-2-{[(5-phenoxypyridin-2-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid pinanediol ester 33-B{(1R)-2-cyclopropyl-1-[((2S)-2-{[(5-phenoxypyridin-2-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid D-mannitol ester 33-C{(1R)-2-cyclopropyl-1-[((2S)-2-{[(5-phenoxypyridin-2-yl)sulfonyl]amino}-3-phenylpropanoyl)amino]ethyl}boronic acid citrate ester

As used herein, the term “boronic acid” refers to a chemical compoundcontaining a —B(OH)₂ moiety. In some embodiments, boronic acid compoundscan form oligomeric anhydrides by dehydration of the boronic acidmoiety. For example, Snyder et al., J. Am. Chem. Soc. 80:3611 (1958),reports oligomeric arylboronic acids.

As used herein, the term “boronic acid anhydride” refers to a chemicalcompound formed by combination of two or more molecules of a boronicacid compound, with loss of one or more water molecules. When mixed withwater, the boronic acid anhydride compound is hydrated to release thefree boronic acid compound. In various embodiments, the boronic acidanhydride can comprise two, three, four, or more boronic acid units, andcan have a cyclic or linear configuration. Non-limiting examples ofoligomeric boronic acid anhydrides of peptide boronic acids compound ofthe invention are illustrated below:

In formulae (1) and (2) directly above, the variable n is an integerfrom 0 to about 10, preferably 0, 1, 2, 3, or 4. In some embodiments,the boronic acid anhydride compound comprises a cyclic trimer(“boroxine”) of formula (2), wherein n is 1. The variable W has theformula (3):

wherein the variables P, A, and R^(a2) have the values and preferredvalues described above for formula (I).

In some embodiments, at least 80% of the boronic acid present in theboronic acid anhydride compound exists in a single oligomeric anhydrideform. In some embodiments, at least 85%, 90%, 95%, or 99% of the boronicacid present in the boronic acid anhydride compound exists in a singleoligomeric anhydride form. In certain preferred embodiments, the boronicacid anhydride compound consists of, or consists essentially of, aboroxine having formula (3).

The boronic acid anhydride compound preferably can be prepared from thecorresponding boronic acid by exposure to dehydrating conditions,including, but not limited to, recrystallization, lyophilization,exposure to heat, and/or exposure to a drying agent. Nonlimitingexamples of suitable recrystallization solvents include ethyl acetate,dichloromethane, hexanes, ether, acetonitrile, ethanol, and mixturesthereof.

In some embodiments, Z¹ and Z² together form a moiety derived from aboronic acid complexing agent. For purposes of the invention, the term“boronic acid complexing agent” refers to any compound having at leasttwo functional groups, each of which can form a covalent bond withboron. Nonlimiting examples of suitable functional groups include amino,hydroxyl, and carboxyl. In some embodiments, at least one of thefunctional groups is a hydroxyl group. The term “moiety derived from aboronic acid complexing agent” refers to a moiety formed by removing thehydrogen atoms from two functional groups of a boronic acid complexingagent.

As used herein, the terms “boronate ester” and “boronic ester” are usedinterchangeably and refer to a chemical compound containing a —B(Z¹)(Z²)moiety, wherein at least one of Z¹ or Z² is alkoxy, aralkoxy, oraryloxy; or Z¹ and Z² together form a moiety derived from a boronic acidcomplexing agent having at least one hydroxyl group.

In the compounds of formulae (I), (I-A), (I-B), and (II), Z¹ and Z² areeach independently hydroxy, alkoxy, aryloxy, or aralkoxy; or Z¹ and Z²together form a moiety derived from a boronic acid complexing agent. Insome embodiments, Z¹ and Z² are each hydroxy. In some other embodiments,Z¹ and Z² together form a moiety derived from a compound having at leasttwo hydroxyl groups separated by at least two connecting atoms in achain or ring, said chain or ring comprising carbon atoms and,optionally, a heteroatom or heteroatoms which can be N, S, or O, whereinthe atom attached to boron in each case is an oxygen atom.

As employed herein, the term “compound having at least two hydroxylgroups” refers to any compound having two or more hydroxyl groups. Forpurposes of the invention, the two hydroxyl groups preferably areseparated by at least two connecting atoms, preferably from about 2 toabout 5 connecting atoms, more preferably 2 or 3 connecting atoms. Forconvenience, the term “dihydroxy compound” may be used to refer to acompound having at least two hydroxyl groups, as defined above. Thus, asemployed herein, the term “dihydroxy compound” is not intended to belimited to compounds having only two hydroxyl groups. The moiety derivedfrom a compound having at least two hydroxyl groups may be attached toboron by the oxygen atoms of any two of its hydroxyl groups. Preferably,the boron atom, the oxygen atoms attached to boron, and the atomsconnecting the two oxygen atoms together form a 5- or 6-membered ring.

For purposes of the present invention, the boronic acid complexing agentpreferably is pharmaceutically acceptable, i.e., suitable foradministration to humans. In some preferred embodiments, the boronicacid complexing agent is a sugar, as described, e.g., in Plamondon etal., WO 02/059131 and Gupta et al., WO 02/059130. The term “sugar”includes any polyhydroxy carbohydrate moiety, including monosaccharides,disaccharides, polysaccharides, sugar alcohols and amino sugars. In someembodiments, the sugar is a monosaccharide, disaccharide, sugar alcohol,or amino sugar. Non-limiting examples of suitable sugars includeglucose, sucrose, fructose, trehalose, mannitol, sorbitol, glucosamine,and N-methylglucosamine. In certain embodiments, the sugar is mannitolor sorbitol. Thus, in the embodiments wherein the sugar is mannitol orsorbitol, Z¹ and Z² together form a moiety of formula C₆H₁₂O₆, whereinthe oxygen atoms of the two deprotonated hydroxyl groups form covalentattachments with boron to form a boronate ester compound. In certainparticular embodiments, Z¹ and Z² together form a moiety derived fromD-mannitol.

In some other preferred embodiments, the boronic acid complexing agentis an alpha-hydroxycarboxylic acid or a beta-hydroxycarboxylic acid, asdescribed, e.g., in Elliott et al., WO 09/154,737, herein incorporatedby reference. In some such embodiments, the boronic acid complexingagent is selected from the group consisting of glycolic acid, malicacid, hexahydromandelic acid, citric acid, 2-hydroxyisobutyric acid,3-hydroxybutyric acid, mandelic acid, lactic acid,2-hydroxy-3,3-dimethylbutyric acid, 2-hydroxy-3-methylbutyric acid,2-hydroxyisocaproic acid, beta-hydroxyisovaleric acid, salicylic acid,tartaric acid, benzilic acid, glucoheptonic acid, maltonic acid,lactobionic acid, galactaric acid, embonic acid, 1-hydroxy-2-naphthoicacid, and 3-hydroxy-2-naphthoic acid. In certain such embodiments, theboronic acid complexing agent is citric acid.

In certain embodiments, wherein the alpha-hydroxy carboxylic acid orbeta-hydroxy carboxylic acid is citric acid, the compound of generalformula (I) is characterized by formula (III-A) or (III-B):

or a mixture thereof, wherein the variables P, A, and R^(a2) have thevalues described herein.

In certain embodiments, wherein the alpha-hydroxy carboxylic acid orbeta-hydroxy carboxylic acid is citric acid, the compound of generalformula (I) is characterized by formula (IV-A) or (IV-B):

or a mixture thereof, wherein the variable P has the values describedherein.

In certain embodiments, wherein the alpha-hydroxy carboxylic acid orbeta-hydroxy carboxylic acid is citric acid, the compound of generalformula (I) is characterized by formula (IV-A) or (IV-B):

or a mixture thereof, wherein:

P is R^(D)—SO₂—;

R^(D) is phenyl substituted with 0-1 R^(d); and

R^(d) is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl,or cycloaliphatic ring.

In certain such embodiments:

R^(D) is phenyl substituted with 1 R^(d);

R^(d) is substituted or unsubstituted oxazolyl, thiazolyl, orimidazolyl;

wherein if substituted, R^(d) is substituted with 1 R^(dd); and

R^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

In certain embodiments, wherein the alpha-hydroxy carboxylic acid orbeta-hydroxy carboxylic acid is citric acid, the compound of generalformula (I) is characterized by formula (IV-A) or (IV-B):

or a mixture thereof, wherein:

P is R^(D)—SO₂—;

R^(D) is a phenyl substituted with —O—R^(E);

R^(E) is a substituted or unsubstituted pyridinyl, pyrazinyl,pyrimidinyl, quinolinyl, benzothiazolyl, benzimidazolyl, or indolyl;

wherein if substituted, R^(E) is substituted with 1-2 R^(dd); and

each R^(dd) is independently C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, orhalo.

In certain such embodiments:

R^(E) is a substituted or unsubstituted pyridinyl;

wherein if substituted, R^(E) is substituted with 1 R^(dd); and

R^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

In certain embodiments, wherein the alpha-hydroxy carboxylic acid orbeta-hydroxy carboxylic acid is citric acid, the compound of generalformula (I) is characterized by formula (IV-A) or (IV-B):

or a mixture thereof, wherein:

P is R^(D)—SO₂—;

R^(D) is a phenyl substituted with —C(O)—R^(E);

R^(E) is a substituted or unsubstituted pyridinyl, pyrazinyl, orpyrimidinyl;

wherein if substituted, R^(E) is substituted with 1-2 R^(dd); and

each R^(dd) is independently C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, orhalo.

In certain such embodiments:

R^(E) is a substituted or unsubstituted pyridinyl;

wherein if substituted, R^(E) is substituted with 1 R^(dd); and

R^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

General Synthetic Methodology

The compounds of formula (I) can be prepared by methods known to one ofordinary skill in the art. See, e.g., Adams et al., U.S. Pat. No.5,780,454; Pickersgill et al., WO 05/097809. An exemplary syntheticroute to N-acyl-peptidylboronic acid compounds of the invention(P═R^(c)—C(O)—) is set forth in Scheme 1 below.

Coupling of compound i with an N-protected amino acid ii, followed byN-terminal deprotection, provides compounds of formula iii. Examples ofsuitable protecting groups (PG) include, without limitation, acylprotecting groups, e.g., formyl, acetyl (Ac), succinyl (Suc), andmethoxysuccinyl; and urethane protecting groups, e.g.,tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), andfluorenylmethoxycarbonyl (Fmoc). The peptide coupling reaction can beconducted by prior conversion of the carboxylic acid moiety of compoundii to an activated ester, e.g., an O-(N-hydroxysuccinnimide) ester,followed by treatment with compound i. Alternatively, the activatedester can be generated in situ by contacting the carboxylic acid of thecompound ii with a peptide coupling reagent. Examples of suitablepeptide coupling reagents include, without limitation, carbodiimidereagents, e.g., dicyclohexylcarbodiimide (DCC) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC); phosphoniumreagents, e.g., benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP); and uranium reagents, e.g.,O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramthyluronium tetrafluoroborate(TBTU).

Compound iii is then coupled with a carboxylic acid (R^(c)CO₂H) toafford compound iv. The peptide coupling conditions described above forthe coupling of compounds i and ii are also suitable for couplingcompound iii with R^(c)CO₂H. Deprotection of the boronic acid moietythen affords compound v. The deprotection step preferably isaccomplished by transesterification in a biphasic mixture comprising theboronic ester compound iv, an organic boronic acid acceptor, a loweralkanol, a C₅₋₈ hydrocarbon solvent, and aqueous mineral acid.

Alternatively, the order of coupling reactions can be reversed, as shownin Scheme 2. Thus, an O-protected amino acid vi is first coupled with asubstituted benzoic acid (ArCO₂H), followed by ester hydrolysis, to formcompound vii. Coupling with compound i and subsequent boronic aciddeprotection are then accomplished as described above for Scheme 1 toafford compound v.

An exemplary synthetic route for preparation ofN-sulfonyl-peptidylboronic acid compounds of the invention(P═R^(c)—S(O)₂—) is set forth in Scheme 3 below:

Compound iii, prepared as described above for Scheme 1, is treated witha sulfonyl chloride in the presence of a base such asdiisopropylethylamine to afford compound vi. Deprotection of the boronicacid moiety is then accomplished as described above for Scheme 1 toafford compound vii. The order of reactions for preparation of compoundvii also can be reversed in a manner analogous to Scheme 2.

The conversion of viii to the compound of formula (I), wherein Z¹ and Z²together are a moiety derived from an alpha-hydroxy carboxylic acid or abeta-hydroxy carboxylic acid, can be accomplished using esterificationconditions employing approximately at least a molar equivalent of thealpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid in asolvent such as ethyl acetate at a temperature of between about 40° C.and about 80° C. Examples of other suitable solvents for this conversioninclude, but are not limited to, methyl isobutyl ketone, acetone,acetonitrile, 2-methyltetrahydrofuran, anisole, isopropyl acetate,dimethoxyethane, tetrahydrofuran, dioxane, dichloromethane, toluene,heptane, methylcyclohexane, tert-butyl methyl ether, and mixturesthereof. The choice of the solvent will depend partly on the solubilityof the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acidused. The temperature selected for the conversion of viii to thecompound of formula (I) will depend partly on the boiling point of thesolvent or solvent mixture used.

The conversion of viii to the compound of formula (I) wherein Z¹ and Z²together are a moiety derived from an alpha-hydroxy carboxylic acid or abeta-hydroxy carboxylic acid, may be catalyzed by an organic amine basesuch as, but not limited to, triethylamine, triethylenediamine,pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine,di-tertbutylpyridine, N-methylmorpholine, N-methylpiperidine,tetramethylguanidine, diazabicyclo[5.4.0]undec-7-ene (DBU),1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicycle[4.3.0]non-5-ene, N,N′diisopropylethylamine, or a mixture thereof.

The compound of formula viii and the alpha-hydroxy carboxylic acid orbeta-hydroxy carboxylic acid are heated together in the solvent ofchoice for a period of time. Following this period of time, the reactionmixture is allowed to cool for a period of time and the compound offormula (I) which precipitates upon cooling is collected by filtration.The cooling may be uncontrolled or may be controlled by the use of acooling apparatus. The reaction mixture may be stirred during thiscooling period. Alternatively, the compound of formula (I) can also beisolated from the reaction mixture by cooling followed by evaporation ofthe solvent. The reaction mixture may be seeded with crystals of thecompound of formula (I) in order to effect precipitation.

A co-solvent such as, but not limited to, heptane, methylcyclohexane,toluene, tert-butylmethyl ether, ethyl acetate, or a mixture thereof,may be added during the cooling period. Following the addition of theco-solvent, the reaction mixture can be cooled further leading to theprecipitation of the compound of formula (I). Alternatively, once theco-solvent is added, the reaction mixture can then be heated again togenerate a homogenous solution, which is then cooled leading to theprecipitation of the compound of formula (I). The reaction mixture maybe seeded with crystals of the compound of formula (I) in order toeffect precipitation.

In some embodiments, the compound of formula (I), wherein Z¹ and Z²together are a moiety derived from an alpha-hydroxy carboxylic acid or abeta-hydroxy carboxylic acid is isolated in crystalline form. In someembodiments, the compound of formula (I) is isolated in substantiallycrystalline form. In some other embodiments, the compound of formula (I)is isolated in amorphous form.

The compound of formula (I), wherein Z¹ and Z² together are a moietyderived from an alpha-hydroxy carboxylic acid or a beta-hydroxycarboxylic acid, can also be generated by the co-lyophilization ofcompound viii and the alpha-hydroxy carboxylic acid or beta-hydroxycarboxylic acid. This is accomplished by subjecting an aqueous solutioncomprising the compound of formula viii and a molar excess of thealpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid to alyophilization procedure. In some embodiments, the aqueous solutionadditionally comprises a water-miscible co-solvent. Examples of suitableco-solvents include, but are not limited to, tert-butyl alcohol,methanol, ethanol, and mixtures thereof. The co-lyophilization resultsin a composition that contains the compound of formula (I) and theexcess alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid.

Uses, Formulation, and Administration

The present invention provides compounds that are potent inhibitors ofthe proteasome. The compounds can be assayed in vitro or in vivo fortheir ability to inhibit proteasome-mediated peptide hydrolysis orprotein degradation.

In another aspect, therefore, the invention provides a method forinhibiting one or more peptidase activities of a proteasome in a cell,comprising contacting a cell in which proteasome inhibition is desiredwith a compound described herein, or a pharmaceutically acceptable salt,boronic ester, or boronic acid anhydride thereof.

The invention also provides a method for inhibiting cell proliferation,comprising contacting a cell in which such inhibition is desired with acompound described herein. The phrase “inhibiting cell proliferation” isused to denote the ability of a compound of the invention to inhibitcell number or cell growth in contacted cells as compared to cells notcontacted with the inhibitor. An assessment of cell proliferation can bemade by counting cells using a cell counter or by an assay of cellviability, e.g., an MTT or WST assay. Where the cells are in a solidgrowth (e.g., a solid tumor or organ), such an assessment of cellproliferation can be made by measuring the growth, e.g., with calipers,and comparing the size of the growth of contacted cells withnon-contacted cells.

Preferably, the growth of cells contacted with the inhibitor is retardedby at least about 50% as compared to growth of non-contacted cells. Invarious embodiments, cell proliferation of contacted cells is inhibitedby at least about 75%, at least about 90%, or at least about 95% ascompared to non-contacted cells. In some embodiments, the phrase“inhibiting cell proliferation” includes a reduction in the number ofcontacted cells, as compare to non-contacted cells. Thus, a proteasomeinhibitor that inhibits cell proliferation in a contacted cell mayinduce the contacted cell to undergo growth retardation, to undergogrowth arrest, to undergo programmed cell death (i.e., apoptosis), or toundergo necrotic cell death.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or boronic acid anhydride thereof, and a pharmaceuticallyacceptable carrier.

If a pharmaceutically acceptable salt of the compound of the inventionis utilized in these compositions, the salt preferably is derived froman inorganic or organic acid or base. For reviews of suitable salts,see, e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977) and Remington: TheScience and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, LippincottWilliams & Wilkins, 2000.

Nonlimiting examples of suitable acid addition salts include thefollowing: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Suitable base addition salts include, without limitation, ammoniumsalts, alkali metal salts, such as lithium, sodium and potassium salts;alkaline earth metal salts, such as calcium and magnesium salts; othermultivalent metal salts, such as zinc salts; salts with organic bases,such as dicyclohexylamine, N-methyl-D-glucamine, t-butylamine, ethylenediamine, ethanolamine, and choline; and salts with amino acids such asarginine, lysine, and so forth. In some embodiments, thepharmaceutically acceptable salt is a base addition salt of a boronicacid compound of formula (I), wherein Z¹ and Z² are both hydroxy.

The term “pharmaceutically acceptable carrier” is used herein to referto a material that is compatible with a recipient subject, preferably amammal, more preferably a human, and is suitable for delivering anactive agent to the target site without terminating the activity of theagent. The toxicity or adverse effects, if any, associated with thecarrier preferably are commensurate with a reasonable risk/benefit ratiofor the intended use of the active agent.

The terms “carrier”, “adjuvant”, or “vehicle” are used interchangeablyherein, and include any and all solvents, diluents, and other liquidvehicles, dispersion or suspension aids, surface active agents, pHmodifiers, isotonic agents, thickening or emulsifying agents,preservatives, solid binders, lubricants and the like, as suited to theparticular dosage form desired. Remington: The Science and Practice ofPharmacy, 20th Ed, ed. A. Gennaro, Lippincott Williams & Wilkins, 2000discloses various carriers used in formulating pharmaceuticallyacceptable compositions and known techniques for the preparationthereof. Except insofar as any conventional carrier medium isincompatible with the compounds of the invention, such as by producingany undesirable biological effect or otherwise interacting in adeleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,carbonates, magnesium hydroxide and aluminum hydroxide, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, pyrogen-free water, salts or electrolytessuch as protamine sulfate, disodium hydrogen phosphate, potassiumhydrogen phosphate, sodium chloride, and zinc salts, colloidal silica,magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose, sucrose, and mannitol, starches such as corn starchand potato starch, cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate, powderedtragacanth; malt, gelatin, talc, excipients such as cocoa butter andsuppository waxes, oils such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil, glycols such aspropylene glycol and polyethylene glycol, esters such as ethyl oleateand ethyl laurate, agar, alginic acid, isotonic saline, Ringer'ssolution, alcohols such as ethanol, isopropyl alcohol, hexadecylalcohol, and glycerol, cyclodextrins such as hydroxypropylβ-cyclodextrin and sulfobutylether β-cyclodextrin, lubricants such assodium lauryl sulfate and magnesium stearate, petroleum hydrocarbonssuch as mineral oil and petrolatum. Coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the present inventionmay be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intravenously, or subcutaneously. The formulationsof the invention may be designed to be short-acting, fast-releasing, orlong-acting. Still further, compounds can be administered in a localrather than systemic means, such as administration (e.g., by injection)at a tumor site.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, cyclodextrins, dimethylformamide, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor, and sesameoils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols andfatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables. Theinjectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use. Compositions formulated for parenteral administration may beinjected by bolus injection or by timed push, or may be administered bycontinuous infusion.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents such as phosphates orcarbonates.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

In some embodiments, the compound of formula (I) is administeredintravenously. In some such embodiments, the compound of formula (I)wherein Z¹ and Z² together form a moiety derived from a boronic acidcomplexing agent can be prepared in the form of a lyophilized powder, asdescribed in Plamondon et al., WO 02/059131, hereby incorporated byreference in its entirety. In some embodiments, the lyophilized powderalso comprises free boronic acid complexing agent. Preferably, the freeboronic acid complexing agent and the compound of formula (I) arepresent in the mixture in a molar ratio ranging from about 0.5:1 toabout 100:1, more preferably from about 5:1 to about 100:1. In variousembodiments, the lyophilized powder comprises free boronic acidcomplexing agent and the corresponding boronate ester in a molar ratioranging from about 10:1 to about 100:1, from about 20:1 to about 100:1,or from about 40:1 to about 100:1.

In some embodiments, the lyophilized powder comprises boronic acidcomplexing agent and a compound of formula (I), substantially free ofother components. However, the composition can further comprise one ormore other pharmaceutically acceptable excipients, carriers, diluents,fillers, salts, buffers, bulking agents, stabilizers, solubilizers, andother materials well known in the art. The preparation ofpharmaceutically acceptable formulations containing these materials isdescribed in, e.g., Remington: The Science and Practice of Pharmacy,20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000, or latestedition. In some embodiments, the pharmaceutical composition comprises acompound of formula (I), a bulking agent, and a buffer.

The lyophilized powder comprising the compound of formula (I) can beprepared according to the procedures described in Plamondon et al., WO02/059131. Thus, in some embodiments, the method for preparing thelyophilized powder comprises: (a) preparing an aqueous mixturecomprising a boronic acid compound of formula (I), wherein Z¹ and Z² areeach hydroxy, and a boronic acid complexing agent; and (b) lyophilizingthe mixture.

The lyophilized powder preferably is reconstituted by adding an aqueoussolvent suitable for pharmaceutical administrations. Examples ofsuitable reconstitution solvents include, without limitation, water,saline, and phosphate buffered saline (PBS). Preferably, the lyophilizedpowder is reconstituted with normal (0.9%) saline. Upon reconstitution,an equilibrium is established between a boronate ester compound and thecorresponding free boronic acid compound. In some embodiments,equilibrium is reached quickly, e.g., within 10-15 minutes, after theaddition of aqueous medium. The relative concentrations of boronateester and boronic acid present at equilibrium is dependent uponparameters such as, e.g., the pH of the solution, temperature, thenature of the boronic acid complexing agent, and the ratio of boronicacid complexing agent to boronate ester compound present in thelyophilized powder.

The pharmaceutical compositions of the invention preferably areformulated for administration to a patient having, or at risk ofdeveloping or experiencing a recurrence of, a proteasome-mediateddisorder. The term “patient”, as used herein, means an animal,preferably a mammal, more preferably a human. Preferred pharmaceuticalcompositions of the invention are those formulated for oral,intravenous, or subcutaneous administration. However, any of the abovedosage forms containing a therapeutically effective amount of a compoundof the invention are well within the bounds of routine experimentationand therefore, well within the scope of the instant invention. In someembodiments, the pharmaceutical composition of the invention may furthercomprise another therapeutic agent. In some embodiments, such othertherapeutic agent is one that is normally administered to patients withthe disease or condition being treated.

By “therapeutically effective amount” is meant an amount sufficient tocause a detectable decrease in proteasome activity or the severity of aproteasome-mediated disorder. The amount of proteasome inhibitor neededwill depend on the effectiveness of the inhibitor for the given celltype and the length of time required to treat the disorder. It shouldalso be understood that a specific dosage and treatment regimen for anyparticular patient will depend upon a variety of factors, including theactivity of the specific compound employed, the age, body weight,general health, sex, and diet of the patient, time of administration,rate of excretion, drug combinations, the judgment of the treatingphysician, and the severity of the particular disease being treated. Theamount of additional therapeutic agent present in a composition of thisinvention typically will be no more than the amount that would normallybe administered in a composition comprising that therapeutic agent asthe only active agent. Preferably, the amount of additional therapeuticagent will range from about 50% to about 100% of the amount normallypresent in a composition comprising that agent as the onlytherapeutically active agent.

In another aspect, the invention provides a method for treating apatient having, or at risk of developing or experiencing a recurrenceof, a proteasome-mediated disorder. As used herein, the term“proteasome-mediated disorder” includes any disorder, disease orcondition which is caused or characterized by an increase in proteasomeexpression or activity, or which requires proteasome activity. The term“proteasome-mediated disorder” also includes any disorder, disease orcondition in which inhibition of proteasome activity is beneficial.

For example, compounds and pharmaceutical compositions of the inventionare useful in treatment of disorders mediated via proteins (e.g., NFκB,p27^(Kip), p21^(WAF/CIPI), p53) which are regulated by proteasomeactivity. Relevant disorders include inflammatory disorders (e.g.,rheumatoid arthritis, inflammatory bowel disease, asthma, chronicobstructive pulmonary disease (COPD), osteoarthritis, dermatosis (e.g.,atopic dermatitis, psoriasis)), vascular proliferative disorders (e.g.,atherosclerosis, restenosis), proliferative ocular disorders (e.g.,diabetic retinopathy), benign proliferative disorders (e.g.,hemangiomas), autoimmune diseases (e.g., multiple sclerosis, tissue andorgan rejection), as well as inflammation associated with infection(e.g., immune responses), neurodegenerative disorders (e.g., Alzheimer'sdisease, Parkinson's disease, motor neurone disease, neuropathic pain,triplet repeat disorders, astrocytoma, and neurodegeneration as resultof alcoholic liver disease), ischemic injury (e.g., stroke), andcachexia (e.g., accelerated muscle protein breakdown that accompaniesvarious physiological and pathological states, (e.g., nerve injury,fasting, fever, acidosis, HIV infection, cancer affliction, and certainendocrinopathies)).

The compounds and pharmaceutical compositions of the invention areparticularly useful for the treatment of cancer. As used herein, theterm “cancer” refers to a cellular disorder characterized byuncontrolled or disregulated cell proliferation, decreased cellulardifferentiation, inappropriate ability to invade surrounding tissue,and/or ability to establish new growth at ectopic sites. The term“cancer” includes, but is not limited to, solid tumors and bloodbornetumors. The term “cancer” encompasses diseases of skin, tissues, organs,bone, cartilage, blood, and vessels. The term “cancer” furtherencompasses primary and metastatic cancers. In some embodiments,therefore, the invention provides the compound of formula (I), or apharmaceutically acceptable salt or boronic acid anhydride thereof, foruse in treating cancer. In some embodiments, the invention provides apharmaceutical composition (as described above) for the treatment ofcancer comprising the compound of formula (I), or a pharmaceuticallyacceptable salt or boronic acid anhydride thereof. In some embodiments,the invention provides the use of the compound of formula (I), or apharmaceutically acceptable salt or boronic acid anhydride thereof, forthe preparation of a pharmaceutical composition (as described above) forthe treatment of cancer. In some embodiments, the invention provides theuse of an effective amount of the compound of formula (I), or apharmaceutically acceptable salt or boronic acid anhydride thereof, forthe treatment of cancer.

Differences in enzyme kinetics, i.e. the dissociation half-lives,between various proteasome inhibitors may result in differences intissue distribution of the various inhibitors, which may lead todifferences in safety and efficacy profiles. For example, with slowlyreversible and irreversible inhibitors a substantial proportion of themolecules may bind to proteasomes in red blood cells, the vascularendothelium, and well-perfused organs such as the liver (i.e. the most‘immediately available’ proteasomes in the proximal compartments). Thesesites might effectively act as a ‘sink’ for these agents, rapidlybinding the molecules and affecting distribution into solid tumors.

Without wishing to be bound by theory, the present inventors believethat compounds that more rapidly dissociate from the proteasomedistribute more effectively to tumors, leading to improved antitumoractivity. In some embodiments, the invention relates to a method fortreating a patient with cancer, comprising administering to the patienta compound of any one of formulas (I), (I-A), (I-B), (II), wherein thecompound exhibits a dissociation half-life of less than 60 minutes. Insome embodiments, the compound exhibits a dissociation half-life of lessthan 10 minutes.

Non-limiting examples of solid tumors that can be treated with thedisclosed proteasome inhibitors include pancreatic cancer; bladdercancer; colorectal cancer; breast cancer, including metastatic breastcancer; prostate cancer, including androgen-dependent andandrogen-independent prostate cancer; renal cancer, including, e.g.,metastatic renal cell carcinoma; hepatocellular cancer; lung cancer,including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolarcarcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer,including, e.g., progressive epithelial or primary peritoneal cancer;cervical cancer; gastric cancer; esophageal cancer; head and neckcancer, including, e.g., squamous cell carcinoma of the head and neck;melanoma; neuroendocrine cancer, including metastatic neuroendocrinetumors; brain tumors, including, e.g., glioma, anaplasticoligodendroglioma, adult glioblastoma multiforme, and adult anaplasticastrocytoma; bone cancer; and soft tissue sarcoma.

Non-limiting examples of hematologic malignancies that can be treatedwith the disclosed proteasome inhibitors include acute myeloid leukemia(AML); chronic myelogenous leukemia (CML), including accelerated CML andCML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chroniclymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin'slymphoma (NHL), including follicular lymphoma and mantle cell lymphoma;B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); amyloidosis;Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), (refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, the compound or composition of the invention isused to treat a patient having or at risk of developing or experiencinga recurrence in a cancer selected from the group consisting of multiplemyeloma, mantle cell lymphoma, follicular lymphoma, amyloidosis, headand neck cancer, soft-tissue sarcoma, non-small cell lung cancer, andprostate cancer. In some embodiments, the compound or composition of theinvention is used to treat a patient having or at risk of developing orexperiencing a recurrence in a cancer selected from the group consistingof multiple myeloma and mantle cell lymphoma.

In some embodiments, the proteasome inhibitor of the invention isadministered in conjunction with another therapeutic agent. The othertherapeutic agent may also inhibit the proteasome, or may operate by adifferent mechanism. In some embodiments, the other therapeutic agent isone that is normally administered to patients with the disease orcondition being treated. The proteasome inhibitor of the invention maybe administered with the other therapeutic agent in a single dosage formor as a separate dosage form. When administered as a separate dosageform, the other therapeutic agent may be administered prior to, at thesame time as, or following administration of the proteasome inhibitor ofthe invention.

In some embodiments, a proteasome inhibitor of formulas (I), or apharmaceutically acceptable salt or boronic acid anhydride thereof, isadministered in conjunction with an anticancer agent. As used herein,the term “anticancer agent” refers to any agent that is administered toa subject with cancer for purposes of treating the cancer.

Non-limiting examples of DNA damaging chemotherapeutic agents includetopoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecinand analogs or metabolites thereof, and doxorubicin); topoisomerase IIinhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylatingagents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine,methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators(e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators andfree radical generators such as bleomycin; and nucleoside mimetics(e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine,cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that disrupt cell replication include:paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, andrelated analogs; thalidomide, lenalidomide, and related analogs (e.g.,CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinibmesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κBinhibitors, including inhibitors of I□B kinase; antibodies which bind toproteins overexpressed in cancers and thereby downregulate cellreplication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab);and other inhibitors of proteins or enzymes known to be upregulated,over-expressed or activated in cancers, the inhibition of whichdownregulates cell replication.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examplesillustrate how to make or test specific compounds, and are not to beconstrued as limiting the scope of the invention in any way.

EXAMPLES

Definitions ACN acetonitrile DCM methylene chloride DIBALdiisobutylaluminum hydride DIEA diisopropylethyl amine DMFdimethylformamide EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride EtOAc ethyl acetate h hours HATUN,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uroniumhexafluorophosphate HOBt 1-hydroxybenztriazole hydrate HPLC highperformance liquid chromatography LCMS liquid chromatography massspectrum LHMDS lithium hexamethyldisilazide min minutes NMM4-methylmorpholine R_(t) retention time from diode array spectra TBTUo-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate TFAtrifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

Analytical LCMS Methods LCMS Conditions

Analyses of boronic acids were run on a Waters Symmetry C18 3.5u 4.6×100mm ID column using the following gradient:

Solvent A: 1% acetonitrile, 99% water, 0.1% formic acidSolvent B: 95% acetonitrile, 5% water, 0.1% formic acid

Flow Time A [%] B [%] [ml/min] 0.0 95.0 5.0 1.0 7.5 0.0 100.0 1.0 9.80.0 100.0 1.0 9.8 95.0 5.0 1.0 10.0 95.0 5.0 1.0

Spectra of intermediates were run on a Hewlett-Packard HP1100 using thefollowing conditions:

Formic Acid: Phenominex Luna 5 μm C18 50×4.6 mm column at 2.5 ml/mingradient of ACN containing 0 to 100 percent 0.1% Formic Acid in H₂O for3 min

Ammonium Acetate: Phenominex Luna 5 μm C18 50×4.6 mm column at 2.5ml/min gradient of ACN containing 0 to 100 percent 10 mM AmmoniumAcetate in H₂O for 3 min.

Example 1 Intermediate 7

Step 1:(3aS,4S,6S)-2-(dichloromethyl)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaboroleIntermediate 1

To a solution of DCM (80 mL, 1.2 mol) in THF (800 mL) at −80° C. to −90°C. was added n-BuLi (2.5 M in hexane, 480 mL, 1.2 mol) under N₂, and thereaction mixture was stirred for 1.5 h below −80° C. B(OEt)₃ (200 mL,1.2 mol) was added in one portion and the mixture was stirred for 1 h at−45° C. to −30° C. Aqueous HCl (5 M, 240 mL, 1.2 mol) was then addeddropwise while maintaining the temperature below −20° C. and theresulting mixture was stirred at −20° C. for 4 h. The organic layer wasseparated, and the water layer was extracted with diethyl ether (100mL×2). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated to give an intermediate. The intermediate was re-dissolvedin diethyl ether (800 mL) and pinanediol (188 g, 1.1 mol) was added tothe solution. The reaction mixture was stirred overnight at roomtemperature and then concentrated in vacuo. The residue was purified bycolumn chromatography (petroleum ether:EtOAc 10:1 to 1:1) to affordIntermediate 1 (190 g, 60% yield).

Step 2: Intermediate 2

Allylmagnesium bromide (26.1 mL of 1M in THF) was added to a solution ofIntermediate 1 (5.0 g in 60 mL of THF) at −78° C. The solution wasstirred for 20 minutes and zinc dichloride (33.25 mL) was added in oneportion. The mixture was allowed to warm from −78° C. to roomtemperature while stirring overnight. The reaction mixture waspartitioned between EtOAc and a saturated solution of ammonium chloride.The organic layer was washed with water followed by brine and thesolvent removed by roatary evaporation to give Intermediate 2.

Step 3: Intermediate 3

To a solution of LHMDS (1 M in THF, 210 mL, 0.21 mol) at −78° C. wasadded a solution of Intermediate 2 (51.8 g, 0.19 mol) in THF (500 mL)under N₂. The reaction mixture was allowed to warm to room temperatureand stirred overnight. The solvent was removed by rotary evaporation andthe residue was taken up in diethyl ether/hexanes (1/1; 1 L). Thesolution was flashed through a pad of silica gel (300 g) and washed withdiethyl ether/hexanes (1/1; 500 mL). The solution was concentrated togive Intermediate 3 (75.8 g, 100%) as a colorless oil.

Step 4: Intermediate 4

To a solution of Intermediate 3 (75.8 g, 0.19 mol) in diethyl ether (750mL) was added 90 mL of TFA dropwise at 0° C. The mixture was allowed towarm to room temperature and stirred for 30 minutes. The solvent wasevaporated to give Intermediate 4 (70.1 g, 100% yield) as a white solid.

Step 5: Intermediate 5

To a solution of Intermediate 4 (30.8 g, 0.08 mol) in DCM (1 L) wasadded HATU (31.58 g, 0.09 mol). The solution was cooled to −45° C. anddiisopropylethylamine (54 mL, 0.3 mol) was added dropwise. The mixturewas allowed to warm to room temperature and stirred overnight. Thereaction mixture was partitioned between EtOAc and water, and theorganic layer washed with brine followed by drying over sodium sulfate.Removal of the solvent followed by silica gel chromatography (petroleumether/EtOAc; 20:1 to 3:1 gradient) gave Intermediate 5 (29 g, 51.7%).

Step 6: Intermediate 6

To a solution of Intermediate 5 (2.0 g, 4.0 mmol) in diethyl ether (200mL) was added dropwise a solution of diazomethane (6 mmol; prepared fromDiazald) in 200 mL of diethyl ether at 0° C. Palladium acetate (42 mg,0.188 mmol) was added and the mixture stirred until the evolution ofnitrogen ceased. The solvent was removed and the product purified byflash chromatography using an EtOAc/petroleum ether gradient (1:10 to1:5) to give Intermediate 6 (Yield: 1.3 g 64%).

Step 7: Intermediate 7

To a solution of Intermediate 6 (35.0 g, 0.686 mol) in DCM (500 mL) wasadded 500 mL of 1.37 M HCl in dioxane. The mixture was stirred at roomtemperature for two hours and the solvent removed by rotary evaporation.The residue was washed with diethyl ether to give Intermediate 7 (Yield30.0 g, 100%).

Example 2[(1R)-2-cyclopropyl-1-({(2S)-2-[(isoquinolin-5-ylsulfonyl)amino]-3-phenylpropanoyl}amino)ethyl]boronicacid Compound 17 Step 1: Compound 17-A (Procedure A)

To a 250 mL flask was added Intermediate 7 (0.5 g, 1.1 mmol), THF (13mL), diisopropylethylamine (0.5 mL, 3.5 mmol) andisoquinoline-5-sulfonyl chloride (250 mg, 1.1 mmol) The mixture wasstirred at room temperature overnight, then partitioned between EtOAcand water. The organic layer was washed with brine and then dried overNa₂SO₄. The solvent was removed by rotary evaporation and the residuepurified by flash chromatography (petroleum ether:EtOAc; 22:1) to giveCompound 17-A in 48% yield.

Step 2:[(1R)-2-cyclopropyl-1-({(2S)-2-[(isoquinolin-5-ylsulfonyl)amino]-3-phenylpropanoyl}amino)ethyl]boronicacid Compound 17 (Procedure B)

Compound 17-A (270 mg) was dissolved in 8 mL of methanol along with 135mg of (2-methylpropyl)boronic acid. To the mixture was added 8 mL of 1NHCl followed by 8 mL of heptane. The mixture was stirred vigorouslyovernight and the methanol/1N HCl layer was separated and washed with 8mL of heptane. The methanol/HCl was removed by rotary evaporation andthe residue purified by preparative HPLC, resulting in 75 mg (31%) ofthe title compound. LCMS (ES⁺—H₂0): 450. ¹H NMR (CD₃OD, 400 MHz, δ):9.29 (s, 1H), 8.5 (d, 1H), 8.32 (m, 3H), 7.7 (m, 1H), 6.7-6.9 (m, 5H),4.15 (m, 1H), 3.0 (m, 1H), 2.7 (m, 2H), 1.39 (m, 1H), 1.18 (m, 1H), 0.7(m, 1H), 0.42 (m, 2H), 0.0 (m, 2H).

Example 3 D-Mannitol ester of[(1R)-2-cyclopropyl-1-({(2S)-2-[(isoquinolin-5-ylsulfonyl)amino]-3-phenylpropanoyl}amino)ethyl]boronicacid Compound 17-B (Procedure C)

To the above product[(1R)-2-cyclopropyl-1-({(2S)-2-[(isoquinolin-5-ylsulfonyl)amino]-3-phenylpropanoyl}amino)ethyl]boronicacid (70 mg, 0.149 mmol) was added tert-butyl alcohol (8 mL), water (8mL) and D-mannitol (510 mg, 2.98 mmol). The solution was frozen at −78°C. and placed on lypholizer for 40 h. The resulting{(1R)-1[((2S)-2-{[(2S)-2-(acetylamino)-4-phenylbutanoyl]amino}-3-phenylpropanoyl)amino]-2-cyclobutylethyl}boronicacid.20[C₆H₁₄O₆] was obtained as 580 mg (100% yield) of a white powder.

Example 4 Additional N-Sulfonyl-Peptidylboronic Acid Compounds

The following compounds were prepared by procedures A and B analogous tothose described in Example 2 above using the appropriate sulfonylchloride. ¹H NMR data is described below. All compounds were alsoconverted to the corresponding D-mannitol esters using Procedure C asdescribed above in Example 3.

Compound ¹H NMR (Bruker 400 mHz) 8 ¹H NMR (⁶D DMSO, 400 MHz, δ): 8.41(s, 1H), 7.94 (m, 1H), 7.71 (s, 1H), 7.59 (m, 2H), 7.42 (m, 1H), 7.2-7.4(m, 6H), 6.95 (m, 1H), 6.55 (d, 1H), 4.22 (m, 1H), 3.19 (m, 1H), 2.97(m, 1H), 2.85 (m, 1H), 2.21 (br s, 2H), 1.59 (m, 1H), 1.20 (m, 1H), 0.88(m, 1H), 0.42 (m, 1H), 0.05 (m, 1H). 4 ¹H NMR (CD₃OD, 400 MHz, δ): 9.5(s, 1H), 8.40 (s, 1H), 8.10 (d, 1H), 7.82 (d, 1H), 7.02 (m, 5H), 4.29(m, 1H), 3.02 (m, 1H), 2.88 (m, 1H), 2.49 (m, 1H), 1.78 (m, 1H), 1.02(m, 1H), 0.60 (m, 1H), 0.39 (m, 2H), 0.0 (m, 2H). 6 ¹H NMR (CD₃OD, 400MHz, δ): 8.50 (s, 1H), 7.8-8.0 (m, 5H), 7.2-7.4 (m, 5H), 4.38 (m, 1H),3.16 (m, 1H), 3.0 (m, 1H), 2.65 (m, 1H), 1.4 (m, 1H), 1.2 (m, 1H), 0.72,(m, 1H), 0.49 (m, 2H), 0.0 (m, 2H). 13 ¹H NMR (CD₃OD, 400 MHz, δ): 7.8(d, 1H), 7.5 (s, 1H), 7.2 (m, 5H), 7.05 (d, 1H), 4.7 (br s, 2H), 4.25(m, 1H), 3.30 (s, 3H), 3.12 (m, 1H), 2.90 (m, 1H), 2.62 (m, 1H), 1.35(m, 1H), 1.15 (m, 1H), 0.7 (m, 1H), 0.45 (m, 2H), 0.0 (m, 2H). 1 ¹H NMR(CD₃OD, 400 MHz, δ): 8.30 (d, 1H), 8.0 (m, 1H), 7.80 (m, 2H), 7.2-7.4(m, 9H), 4.25 (m, 1H), 3.25 (m, 1H), 2.99 (m, 1H), 2.71 (m, 1H), 1.39(m, 1H), 1.21 (m, 1H), 0.69 (m, 1H), 0.48 (m, 2H), 0.0 (m, 2H). 15 ¹HNMR (CD₃OD, 400 MHz, δ): 7.5 (s, 1H), 7.22 (m, 5H), 6.89 (s, 1H), 4.70(s, 2H), 4.3 (m, 1H), 3.15 (m, 1H), 2.99 (m, 1H), 2.75 (m, 1H), 1.40 (m,1H), 1.20 (m, 1H), 0.7 (m, 1H), 0.50 (m, 2H), 0.0 (m, 2H). 7 ¹H NMR(CD₃OD, 400 MHz, δ): 8.50 (s, 1H), 8.2 (m, 1H), 7.80 (m, 2H), 7.1-7.3(m, 8H), 4.30 (m, 1H), 3.25 (m, 1H), 3.0 (m, 1H), 2.75 (m, 1H), 1.4 (m,1H), 1.20 (m, 1H), 0.65 (m, 1H), 0.5 (m, 2H), 0.0 (m, 2H). 16 ¹H NMR(CD₃OD, 400 MHz, δ): 8.8 (d, 1H), 8.5 (s, 1H), 8.35 (d, 1H), 8.25 (m,2H), 8.05 (d, 1H), 7.75 (m, 2H), 7.21 (m, 5H), 4.35 (m, 1H), 3.25 (m,1H), 2.98 (m, 1H), 2.65 (m, 1H), 1.39 (m, 1H), 1.1 (m, 1H), 0.65 (m,1H), 0.5 (m, 2H), 0.0 (m, 2H). 2 ¹H NMR (CD₃OD, 400 MHz, δ) 8.49 (d,2H), 7.65 (s, 2H), 7.55 (m, 4H), 7.20 m, 5H), 6.98 (d, 2H), 4.25 (m,1H), 3.25 (m, 1H), 2.99 (m, 1H), 2.70 (m, 1H), 1.38 (m, 1H), 1.21 (m,1H), 0.70 (m, 1H), 0.49 (m, 2H), 0.0 (m, 2H). 14 ¹H NMR (CD₃OD, 400 MHz,δ) 8.50 (d, 2H), 7.85 (d, 2H), 7.2-7.4 (m, 9H), 4.25 (m, 1H), 3.25 (m,1H), 2.99 (m, 1H), 2.70 (m, 1H), 1.38 (m, 1H), 1.21 (m, 1H), 0.70 (m,1H), 0.49 (m, 2H), 0.0 (m, 2H). 5 ¹H NMR (CD₃OD, 400 MHz, δ): 8.40 (s,1H), 8.25 (m, 1H), 7.98 (s, 1H), 7.88 (m, 1H), 7.70 (m, 1H), 7.25 (m,5H), 4.45 (m, 1H), 3.25 (m, 1H), 3.05 (m, 1H), 2.97 (s, 3H), 2.60 (m,1H), 1.40 (m, 1H), 1.15 (m, 1H), 0.65 (m, 1H), 0.49 (m, 2H), 0.0 (m,2H). 10 ¹H NMR (CD₃OD, 400 MHz, δ): 7.7 (d, 1H), 7.55 (d, 1H), 7.35 (s,1H), 7.22 (m, 1H), 7.02 (m, 3H), 6.8 (m, 3H), 4.22 (m, 1H), 3.9 (s, 3H),2.95 (m, 1H), 2.65 (m, 1H), 2.5 (m, 1H), 1.35 (m, 1H), 0.97 (m, 1H),0.55 (m, 1H), 0.39 (m, 2H), 0.0 (m, 2H). 3 ¹H NMR (CD₃OD, 400 MHz, δ):8.49 (s, 1H), 7.7 (d, 1H), 7.2-7.4 (m, 5H), 6.75 (d, 1H), 4.25 (m, 1H),3.85 (m, 4H), 3.75 (m, 4H), 3.12 (m, 1H), 2.95 (m, 1H), 2.54 (m, 1H),1.38 (m, 1H), 1.22 (m, 1H), 0.69 (m, 1H), 0.47 (m, 2H), 0.0 (m, 2H).

Example 5[(1R)-2-cyclopropyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)ethyl]boronicacid Compound 12 Step 1:N-[(1S)-1-benzyl-2-({(1R)-2-cyclopropyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}amino)-2-oxoethyl]pyrazine-2-carboxamideCompound 12-A (Procedure D)

Intermediate 7 (0.053 g, 0.11 mmol) was dissolved in 1 mL of DMF alongwith pyrazine-2-carboxylic acid (0.12 mmol), TBTU (0.13 mmol), anddiisopropylethylamine (96 μL). The mixture was stirred at roomtemperature overnight and then partitioned between DCM and 1N NaOH. Theorganic layer was washed with water and the solvent removed by rotaryevaporation to give 0.047 g of Compound 12-A which was used withoutpurification in the following step.

Step 2:[(1R)-2-cyclopropyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)ethyl]boronicacid Compound 12 (Procedure B)

The title compound was prepared from Compound 12-A using procedure B asdescribed above in Example 2. The title compound was purified bypreparative TLC on silica gel plates using 1:9 methanol:DCM as eluent(Yield: 0.0039 g, 15%). The title compound showed a single peak by LCMSwith the expected MW of 382 (ES⁻) and 365 (ES⁺ minus H₂O). Compound 12was converted to its mannitol ester Compound 12-B following procedure Cas described in Example 3 above.

Example 6[(1R)-2-cyclopropyl-1-({(2S)-2-[(2,5-dichlorobenzoyl)amino]-3-phenylpropanoyl}amino)ethyl]boronicacid Compound 9 Step 1:N-[(1S)-1-benzyl-2-({(1R)-2-cyclopropyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}amino)-2-oxoethyl]-2,5-dichlorobenzamideCompound 9-A (Procedure D)

Intermediate 7 (0.053 g, 0.11 mmol) was dissolved in 1 mL of DMF alongwith 2,5-dichlorobenzoic acid (0.12 mmol), TBTU (0.13 mmol), anddiisopropylethylamine (96 μL). The mixture was stirred at roomtemperature overnight and then partitioned between DCM and 1N NaOH. Theorganic layer was washed with water and the solvent removed by rotaryevaporation to give 0.050 g (78%) of Compound 9-A which was used withoutpurification in the following step.

Step 2:[(1R)-2-cyclopropyl-1-({(2S)-2-[(2,5-dichlorobenzoyl)amino]-3-phenylpropanoyl}amino)ethyl]boronicacid Compound 9 (Procedure B)

The title compound was prepared from Compound 9-A using procedure B asdescribed above in Example 2. The title compound was purified bypreparative TLC on silica gel plates using 1:9 methanol:DCM as eluent(Yield: 0.0073 g, 24%). The title compound showed a single peak by LCMSwith the expected MW of 448 (ES) and 431 (ES⁺ minus H₂O). Compound 9 wasconverted to its mannitol ester Compound 9-B following procedure C asdescribed in Example 3 above.

Example 7 Citrate Ester (Procedure E)

The boronic acid of formula (I), where Z¹ and Z² are hydroxy groups(1.62 mmol) or a corresponding amount of the boronic acid anhydride isdissolved in acetone (30 mL, 0.4 mol) at room temperature. Citric acidmonohydrate (0.340 g, 0.00162 mol) is dissolved in acetone (5 mL), andis then added to the solution of the boronic acid. The flask containingresidual citric acid is rinsed into the reaction mixture with anadditional 5 mL of acetone. The reaction mixture is stirred at roomtemperature for 5 minutes and then the acetone is removed by rotaryevaporation. The resulting solid is dried under vacuum for two days.

Procedure E can also be performed using acetonitrile as the solventinstead of acetone.

Example 8 20S Proteasome Assay

β5 Selective substrate: To 1 μL of test compound dissolved in DMSO in a384-well black microtiter plate is added 25 μL of assay buffer at 37° C.containing human PA28 activator (Boston Biochem, 12 nM final) withAc-WLA-AMC (β5 selective substrate) (15 μM final), followed by 25 μL ofassay buffer at 37° C. containing human 20S proteasome (Boston Biochem,0.25 nM final). Assay buffer is composed of 20 mM HEPES, 0.5 mM EDTA and0.01% BSA, pH7.4. The reaction is followed on a BMG Galaxy plate reader(37° C., excitation 380 nm, emission 460 nm, gain 20). Percentinhibition is calculated relative to 0% inhibition (DMSO) and 100%inhibition (10 μM bortezomib) controls. Compound of formula (I) aretypically tested in this assay as their mannitol esters (prepared asdescribed above). The mannitol esters are hydrolyzed to the free activeboronic acid species.

β1 Selective substrate: To 1 μL of test compound dissolved in DMSO in a384-well microtiter plate is added 25 μL of assay buffer at 37° C.containing human PA28 activator (Boston Biochem, 12 nM final) withZ-LLE-AMC (□1 selective substrate) (15 μM final), followed by 25 μL ofassay buffer at 37° C. containing human 20S proteasome (Boston Biochem,0.25 nM final). Assay buffer is composed of 20 mM HEPES, 0.5 mM EDTA and0.01% BSA, pH7.4. The reaction is followed on a BMG Galaxy plate reader(37° C., excitation 380 nm, emission 460 nm, gain 20). Percentinhibition is calculated relative to 0% inhibition (DMSO) and 100%inhibition (10 μM bortezomib) controls. Compound of formula (I) aretypically tested in this assay as their mannitol esters (prepared asdescribed above). The mannitol esters are hydrolyzed to the free activeboronic acid species.

When tested in this assay, Compounds 1, 2, 4, 6, 7, 9, and 12-17 showedthe percentage inhibition values listed in Table 3 below.

TABLE 3 Percentage Inhibition in 20S Proteasome Assay ConcentrationInhibition Concentration Inhibition Compound (μM) β1 (%) (μM) β5 (%) 10.41 67.2 0.41 91.8 2 0.41 70.7 0.41 89 4 0.41 73.2 0.41 89.8 6 0.4165.4 0.41 92.9 7 0.41 81.3 0.41 93 9 0.33 91.1 0.41 93.3 12 0.33 93 0.4181.9 13 0.41 66.7 0.41 83.7 14 0.41 75.7 0.41 93.1 15 0.41 77.1 0.4190.3 16 0.41 82.7 0.41 90.8 17 0.41 71.9 0.41 89.7

Example 9 Proteasome Inhibition Kinetics

Enzyme kinetic parameters including dissociation constants and halflives were determined by analysis of enzyme progress curves as follows:

Proteasome inactivation measurements were obtained by monitoringindividual progress curves for the hydrolysis of the site-specificfluorogenic 7-amido-4-methylcoumarin (AMC)-labeled peptide substrates(β5, Suc-LLVY-AMC; β2, Z-VLR-AMC, and β1, Z-LLE-AMC) at differentinhibitor concentrations. Cleavage of the fluorogenic peptide wascontinuously monitored as a change in the fluorescence emission at 460nm (λ_(ex)=360 nm) and plotted as a function of time. All assays wereperformed in cuvettes with 2 mL of 50 mM HEPES (pH 7.5), 0.5 mM EDTA, at37±0.2° C., and with continuous stirring. The concentrations ofsubstrates varied from 10 to 25 μM (<½ K_(M)). The concentration ofhuman 20S proteasome was 0.25 nM and was activated with 0.01% SDS. Therate constant, k_(obs), describing the conversion from the initialvelocity to the steady state velocity, were estimated by nonlinearleast-squares regression analysis of the individual progress curvesusing the equation for time-dependent or slow-binding inhibition:

$F = {{v_{s}t} + {\frac{v_{i} - v_{s}}{k_{obs}}\left\lbrack {1 - {\exp \; \left( {{- k_{obs}}t} \right)}} \right\rbrack}}$

where F is fluorescence, v_(i) and v_(s) are the initial and steadystate velocities of the reaction in the presence of inhibitor, and t istime. A plot of k_(obs) as a function of [I] was made to obtain k_(on)from the slope of the linear fit of the data. The apparent dissociationconstant, K^(app) _(i), was determined by nonlinear least-fit of thefractional velocity, v_(s)/v_(o), as a function of [I], were v_(s) isthe steady state value obtained from the time-dependent or slow-bindingequation and v_(o) is the initial velocity in the absence of inhibitor:

$\frac{v_{s}}{v_{o}} = \frac{1}{a + \frac{\lbrack I\rbrack}{K_{i}^{app}}}$

The dissociation constant K_(i), was calculated from the apparent Kiusing the following expression:

$K_{i} = \frac{K_{i}^{app}}{1 + \frac{\lbrack S\rbrack}{K_{m}}}$

The off rate, k_(off), was mathematically calculated from the abovedetermined parameters using the following relationship:

$K_{i} = \frac{k_{off}}{k_{on}}$

The half-life was then determined from the k_(off) value using thefollowing relationship:

$t_{1/2} = \frac{\ln \mspace{11mu} 2}{k_{off}}$

Using this protocol, dissociation half-lives were determined forCompounds 1, 2, 5, 6, 7, 14, and 16. Compounds 1, 2, 6, and 7 exhibiteda t_(1/2) less than 10 min. Compounds 5, 14, and 16 exhibited a t_(1/2)greater than 10 minutes and less than 60 minutes.

Example 10 Antiproliferation Assay

HCT-116 (1000) or other tumor cells in 100 μL of appropriate cellculture medium (McCoy's 5A for HCT-116, Invitrogen) supplemented with10% fetal bovine serum (Invitrogen) are seeded in wells of a 96-wellcell culture plate and incubated overnight at 37° C. Test compounds areadded to the wells and the plates are incubated for 96 hours at 37° C.MTT or WST reagent (10 μL, Roche) are added to each well and incubatedfor 4 hours at 37° C. as described by the manufacturer. For MTT themetabolized dye is solubilized overnight according to manufacturer'sinstructions (Roche). The optical density for each well is read at 595nm (primary) and 690 nm (reference) for the MTT and 450 nm for the WSTusing a spectrophotometer (Molecular Devices). For the MTT the referenceoptical density values are subtracted from the values of the primarywavelength. Percent inhibition is calculated using the values from aDMSO control set to 100%.

Example 11 In Vivo Tumor Efficacy Model

Freshly dissociated HCT-116 (2−5×10⁶), WSU-DLCL2 (2−5×10⁶), or othertumor cells in 100 μL of RPMI-1640 media (Sigma-Aldrich) are asepticallyinjected into the subcutaneous space in the right dorsal flank of femaleCD-1 nude mice (age 5-8 weeks, Charles River) using a 1 mL 26⅜-ga needle(Becton Dickinson Ref #309625). Alternatively, some xenograft models(e.g., CWR22) require the serial passaging of tumor fragments. In thesecases, small fragments of tumor tissue (approximately 1 mm³) areimplanted subcutaneously in the right dorsal flank of anesthetized (3-5%isoflourane/oxygen mixture) C.B-17/SCID mice (age 5-8 weeks, CharlesRiver) via a 13-ga trocar (Popper & Sons 7927). Beginning at day 7 afterinoculation tumors are measured twice weekly using a vernier caliper.Tumor volumes are calculated using standard procedures(0.5×(length×width²)). When the tumors reach a volume of approximately200 mm³ mice are randomized into treatment groups and begin receivingdrug treatment. Dosing and schedules are determined for each experimentbased on previous results obtained from pharmacokinetic/pharmacodynamicand maximum tolerated dose studies. The control group will receivevehicle without any drug. Typically, test compound (100-200 μL) isadministered via intravenous (27-ga needle), oral (20-ga gavage needle)or subcutaneous (27-ga needle) routes at various doses and schedules.Tumor size and body weight are measured twice a week and the study isterminated when the control tumors reach approximately 2000 mm³.

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, these particular embodiments areto be considered as illustrative and not restrictive. It will beappreciated by one skilled in the art from a reading of this disclosurethat various changes in form and detail can be made without departingfrom the true scope of the invention, which is to be defined by theappended claims rather than by the specific embodiments.

The patent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. The issued patents, applications,and references that are cited herein are hereby incorporated byreference to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofinconsistencies, the present disclosure, including definitions, willcontrol.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein: A is 0, 1, or 2; P is hydrogen or an amino-group-blockingmoiety; each R^(a2) independently is hydrogen, C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, —(CH₂)_(m)—CH₂—R^(B), —(CH₂)_(m)—CH₂—NHC(═NR⁴)NH—Y,—(CH₂)_(m)—CH₂—CON(R⁴)₂, —(CH₂)_(m)—CH₂—N(R⁴)CON(R⁴)₂,—(CH₂)_(m)—CH(R⁶)N(R⁴)₂, —(CH₂)_(m)—CH(R⁵)—OR⁵, or—(CH₂)_(m)—CH(R⁵)—SR⁵; each Y independently is hydrogen, —CN, —NO₂, or—S(O)₂—R¹⁰; each R^(B) independently is a substituted or unsubstitutedmono- or bicyclic ring system; each R⁴ independently is hydrogen or asubstituted or unsubstituted aliphatic, aryl, heteroaryl, orheterocyclyl group; or two R⁴ on the same nitrogen atom, taken togetherwith the nitrogen atom, form a substituted or unsubstituted 4- to8-membered heterocyclyl ring having, in addition to the nitrogen atom,0-2 ring heteroatoms independently selected from N, O, and S; each R⁵independently is hydrogen or a substituted or unsubstituted aliphatic,aryl, heteroaryl, or heterocyclyl group; each R⁶ independently is asubstituted or unsubstituted aliphatic, aryl, or heteroaryl group; eachR¹⁰ independently is C₁₋₆ aliphatic, C₆₋₁₀ aryl, or —N(R⁴)₂; m is 0, 1,or 2; and Z¹ and Z² are each independently hydroxy, alkoxy, aryloxy, oraralkoxy; or Z¹ and Z² together form a moiety derived from a boronicacid complexing agent.
 2. The compound of claim 1, wherein P isR^(c)—C(O)—, R^(c)—O—C(O)—, R^(c)—N(R^(4c))—C(O)—, R^(c)—S(O)₂—, orR^(c)—N(R^(4c))—S(O)₂—; R^(c) is selected from the group consisting ofC₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, —R^(D), -T¹-R^(D), and T¹-R^(2c);T¹ is a C₁₋₆ alkylene chain substituted with 0-2 independently selectedR^(3a) or R^(3b), wherein the alkylene chain optionally is interruptedby —C(R⁵)═C(R⁵)—, —C═C—, or —O—; R^(D) is a substituted or unsubstitutedmonocyclic, bicyclic or tricyclic ring system; R^(2c) is halo, —OR⁵,—SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OC(O)N(R⁴)₂,—C(O)R⁵, —CO₂R⁵, or —C(O)N(R⁴)₂; each R^(3a) independently is selectedfrom the group consisting of —F, —OH, —O(C₁₋₄ alkyl), —CN, —N(R⁴)₂,—C(O)(C₁₋₄ alkyl), —CO₂H, —CO₂(C₁₋₄ alkyl), —C(O)—NH₂, and —C(O)—NH(C₁₋₄alkyl); each R^(3b) independently is a C₁₋₃ aliphatic substituted orunsubstituted with R^(3a) or R⁷; each R⁷ is a substituted orunsubstituted aromatic group; and R^(4c) is hydrogen, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which issubstituted or unsubstituted.
 3. The compound of claim 2, characterizedby formula (I-B):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof.4. The compound of claim 3, wherein A is
 0. 5. The compound of claim 3,wherein each R^(a2) is independently C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, or —(CH₂)_(m)—CH₂—R^(B), and m is 0 or
 1. 6. Thecompound of claim 5, wherein R^(B) is a substituted or unsubstitutedphenyl.
 7. The compound of claim 3, wherein R^(D) is substituted onsubstitutable ring carbon atoms with 0-2 R^(d) and 0-2 R^(8d); eachR^(d) independently is selected from the group consisting of C₁₋₆aliphatic, C₁₋₆ fluoroaliphatic, halo, —R^(1d), —R^(2d), -T²-R^(1d),-T²-R^(2d); T² is a C₁₋₆ alkylene chain substituted with 0-2independently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R⁵)═C(R⁵)—, —C≡C—, or —O—; each R^(1d)independently is a substituted or unsubstituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring; each R^(2d) independently is —NO₂,—CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, or—C(═NR⁴)—N(R⁴)₂; each R^(3a) independently is selected from the groupconsisting of —F, —OH, —O(C₁₋₄ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₄ alkyl),—CO₂H, —CO₂(C₁₋₄ alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₄ alkyl); each R^(3b)independently is a C₁₋₃ aliphatic substituted or unsubstituted withR^(3a) or R⁷, or two substituents R^(3b) on the same carbon atom, takentogether with the carbon atom to which they are attached, form a 3- to6-membered cycloaliphatic ring; each R⁷ independently is a substitutedor unsubstituted aryl or heteroaryl ring; each R^(8d) independently isselected from the group consisting of C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, halo, —OH, —O(C₁₋₄ aliphatic), —NH₂, —NH(C₁₋₄aliphatic), and —N(C₁₋₄ aliphatic)₂; and each substitutable ringnitrogen atom in R^(D) is unsubstituted or is substituted with —C(O)R⁵,—C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, C₁₋₄ aliphatic, a substitutedor unsubstituted C₆₋₁₀ aryl, or a C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portionof which is substituted or unsubstituted.
 8. The compound of claim 3,wherein: each saturated ring carbon atom in R^(D) is unsubstituted or issubstituted with ═O, R^(d) or R^(8d); each unsaturated ring carbon atomin R^(D) is unsubstituted or is substituted with R^(d) or R^(8d); eachR^(d) independently is selected from the group consisting of C₁₋₆aliphatic, C₁₋₆ fluoroaliphatic, halo, —R^(1d), —R^(2d), -T²-R^(1d),-T²-R^(2d); T² is a C₁₋₆ alkylene chain substituted with 0-2independently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R⁵)═C(R⁵)—, —C≡C—, or —O—; each R^(1d)independently is a substituted or unsubstituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring; each R^(2d) independently is —NO₂,—CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, or—C(═NR⁴)—N(R⁴)₂; each R^(3a) independently is selected from the groupconsisting of —F, —OH, —O(C₁₋₄ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₄ alkyl),—CO₂H, —CO₂(C₁₋₄ alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₄ alkyl); each R^(3b)independently is a C₁₋₃ aliphatic substituted or unsubstituted withR^(3a) or R⁷, or two substituents R^(3b) on the same carbon atom, takentogether with the carbon atom to which they are attached, form a 3- to6-membered cycloaliphatic ring; each R⁷ independently is a substitutedor unsubstituted aryl or heteroaryl ring; each R^(8d) independently isselected from the group consisting of C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, halo, —OH, —O(C₁₋₄ aliphatic), —NH₂, —NH(C₁₋₄aliphatic), and —N(C₁₋₄ aliphatic)₂; and each substitutable ringnitrogen atom in R^(D) is unsubstituted or is substituted with —C(O)R⁵,—C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, C₁₋₄ aliphatic, a substitutedor unsubstituted C₆₋₁₀ aryl, or a C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portionof which is substituted or unsubstituted.
 9. The compound of claim 3,wherein R^(D) is a substituted or unsubstituted monocyclic, bicyclic, ortricyclic ring system selected from the group consisting of phenyl,pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl,benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl,oxodihydroindolyl, oxodihydrobenzoxazinyl, dihydrobenzoxazinyl,benzofuropyridyl, pyridoindolyl, and benzofuropyrazinyl.
 10. Thecompound of claim 3, characterized by formula (II):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof,wherein: P has the formula R^(D)—SO₂— or R^(D)—C(O)—; R^(D) is asubstituted or unsubstituted monocyclic, bicyclic, or tricyclic ringsystem selected from the group consisting of phenyl, pyridinyl,pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, benzothiazolyl,indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, oxodihydroindolyl,oxodihydrobenzoxazinyl, dihydrobenzoxazinyl, benzofuropyridyl,pyridoindolyl, and benzofuropyrazinyl; each saturated ring carbon atomin R^(D) is unsubstituted or is substituted with ═O, R^(d), or R^(8d);each unsaturated ring carbon atom in R^(D) is unsubstituted or issubstituted with R^(d) or R^(8d); each R^(d) independently is selectedfrom the group consisting of —R^(1d), —R^(2d), -T²-R^(1d), and-T²-R^(2d); T² is a C₁₋₃ alkylene chain that is unsubstituted or issubstituted with R^(3a) or R^(3b); each R^(1d) independently is asubstituted or unsubstituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic ring; each R^(2d) independently is —OR⁵, —SR⁶, —S(O)R⁶,—SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —O—C(O)R⁵,—OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, or —C(O)N(R⁴)₂; and each R^(8d)independently is selected from the group consisting of C₁₋₄ aliphatic,C₁₋₄ fluoroaliphatic, halo, —OH, —O(C₁₋₄ aliphatic), —NH₂, —NH(C₁₋₄aliphatic), and —N(C₁₋₄ aliphatic)₂.
 11. The compound of claim 10,wherein R^(d) has the formula -Q-R^(E); Q is —O—, —NH—, —S(O)—, —S(O)₂—,—C(O)—, or —CH₂—; and R^(E) is a substituted or unsubstituted aryl,heteroaryl, heterocyclyl or cycloaliphatic ring.
 12. The compound ofclaim 10, wherein R^(D) is a phenyl, pyridinyl, pyrazinyl, orpyrimidinyl, which is substituted with a substituent of formula—O—R^(E), and R^(E) is a substituted or unsubstituted phenyl, pyridinyl,pyrazinyl, pyrimidinyl, quinolinyl, benzothiazolyl, benzimidazolyl, orindolyl.
 13. The compound of claim 10, wherein: R^(D) is phenylsubstituted with 0-1 R^(d); and R^(d) is a substituted or unsubstitutedaryl, heteroaryl, heterocyclyl, or cycloaliphatic ring.
 14. The compoundof claim 13, wherein: P is R^(D)—SO₂—; R^(D) is phenyl substituted with1 R^(d); R^(d) is substituted or unsubstituted oxazolyl, thiazolyl, orimidazolyl; wherein if substituted, R^(d) is substituted with 1 R^(dd);and R^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.
 15. Thecompound of claim 10, wherein: P is R^(D)—SO₂—; R^(D) is phenylsubstituted with —O—R^(E), R^(E) is a substituted or unsubstitutedpyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, benzothiazolyl,benzimidazolyl, or indolyl; wherein if substituted, R^(E) is substitutedwith 1-2 occurrences of R^(dd); and each R^(dd) is independently C₁₋₄aliphatic, C₁₋₄ fluoroaliphatic, or halo.
 16. The compound of claim 15,wherein: R^(E) is a substituted or unsubstituted pyridinyl; wherein ifsubstituted, R^(E) is substituted with 1 occurrence of R^(dd); andR^(dd) is methyl, ethyl, trifluoromethyl, chloro, or fluoro.
 17. Thecompound of claim 10, wherein: P is R^(D)—SO₂—; R^(D) is phenylsubstituted with —O—R^(E), R^(E) is a substituted or unsubstitutedpyridinyl, pyrazinyl, or pyrimidinyl; wherein if substituted, R^(E) issubstituted with 1-2 occurrences of R^(dd); and each R^(dd) isindependently C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, or halo.
 18. Thecompound of claim 17, wherein: R^(E) is a substituted or unsubstitutedpyridinyl; wherein if substituted, R^(E) is substituted with 1occurrence of R^(dd); and R^(dd) is methyl, ethyl, trifluoromethyl,chloro, or fluoro.
 19. A pharmaceutical composition comprising thecompound of claim 1 and a pharmaceutically acceptable carrier ordiluent.
 20. A method for treating cancer comprising administering atherapeutically effective amount of the compound of claim 1 to a patientin need thereof.
 21. The method of claim 20, wherein the cancer isselected from the group consisting of multiple myeloma, mantle celllymphoma, follicular lymphoma, amyloidosis, head and neck cancer,soft-tissue sarcoma, non-small cell lung cancer, and prostate cancer